Clinical evaluation of glucagon and insulin in therapy of fulminant hepatitis

Forty five patients were examined in order to evaluate the usefulness of glucagon and insulin as a therapy of fulminant hepatitis. Thirty patients were treated with simultaneous infusion of glucagon and insulin, whereas prednisolone was given at a daily dose of 60 to 90 mg in 15 cases. In the former group, 1 mg of glucagon and 10 units of regular insulin were infused over a period of 2 to 6 hours. Two such treatments were given per day in the early critical period of fulminant hepatitis. The therapeutic effect of glucagon and insulin was evaluated in comparison with that of prednisolone, and additionally, with a combination therapy of either blood exchange or plasmapheresis in both groups. The survival rate was superior in the group treated with glucagon and insulin (46%) and in the one with combined infusion of these hormones plus plasmapheresis (33%).     

Intermittent Plasmapheresis Prevents Recurrence in Neuromyelitis Optica

Neuromyelitis optica (NMO) is a relapsing inflammatory condition characterized by selective involvement of the optic nerves and spinal cord. Humoral immune mechanisms play a role in the pathogenesis of NMO. The therapeutic efficacy of plasmapheresis (PP) has been reported in the cases that were poorly controlled with other treatments. Herein, we report four patients with NMO who underwent PP following intensive intravenous corticosteroid therapy. All patients showed definite functional improvement following one to five plasma exchanges. To prevent relapse, these patients were treated with oral prednisolone in combination with azathioprine or cyclophosphamide. Two of the four patients also underwent intermittent PP because treatment with oral agents was unsuccessful. In conclusion, when treatment with oral immunosuppressants is ineffective in reducing recurrences of NMO, an additional PP session should be attempted.     

Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens

BACKGROUND: The role of the type of immunosuppression in the natural history of post-transplant hepatitis C virus (HCV) infection is unclear. AIMS: To evaluate the fluctuation of HCV viraemia and the early course of infection, and their relation to the type of immunosuppression in HCV transplant patients. METHODS: In 47 HCV transplant patients, serum HCV RNA levels were determined pretransplant and at one and two weeks, and three and 12 months after transplant. Initial immunosuppression was triple (cyclosporin, azathioprine, prednisolone) in 31, double (cyclosporin, prednisolone) in five, and single (cyclosporin or tacrolimus) in 11 patients. Prednisolone was withdrawn at a median of six months. RESULTS: At three months, HCV RNA levels were higher in patients with single than with triple or double initial therapy. At 12 months, HCV RNA levels correlated only with duration of prednisolone treatment and were relatively higher in patients with triple compared with single initial immunosuppression. A higher necroinflammatory activity at 12 months post-transplant was found in patients with post-transplant acute hepatitis compared with those without. Extent of fibrosis at 12 months was associated with the 12 month HCV RNA level and occurrence of post-transplant acute hepatitis. CONCLUSIONS: HCV RNA levels at three months after transplant are higher in patients treated with single initial immunosuppressive therapy, but at 12 months are higher in patients with longer duration of steroid treatment. HCV viraemia at 12 months seems to be particularly important, as its levels are strongly correlated with the severity of fibrosis.     

Immunoadsorbent plasmapheresis for a patient with antiphospholipid syndrome during pregnancy.

The case of a 34 year old woman with systemic lupus erythematosus with a history of three previous recurrent abortions and lupus anticoagulant and anticardiolipin antibodies is reported. Immunoadsorbent plasmapheresis with a dextran sulphate column was used to remove lupus anticoagulant, anticardiolipin antibodies, and antibodies to DNA during her fourth pregnancy in combination with low doses of aspirin and prednisolone. Although during the course of treatment prednisolone was transiently increased to 30 mg/day owing to an asymptomatic increase of lupus anticoagulant and anticardiolipin antibodies, the levels of lupus anticoagulant, anticardiolipin antibodies, and antibodies to DNA were decreased by immunoadsorbent plasmapheresis and a baby girl was delivered successfully by caesarean section. Therefore, immunoadsorbent plasmapheresis with dextran sulphate seems to reduce the risk of recurrent abortion in patients with the antiphospholipid syndrome.     

Immunosuppressive treatment in a heart transplantation candidate with antiphospholipid syndrome

Summary Dilated cardiomyopathy secondary to a devastating anterior myocardial infarction developed in a young patient with the antiphospholipid antibody syndrome. Due to severe left ventricular failure, heart transplantation was considered. To reduce antiphospholipid antibody titer, plasmapheresis followed by immunosuppressive treatment with cyclosporin and azathioprine were attempted in the pretransplant period. The antibody titer normalized after plasmapheresis, but then rose sharply despite immunosuppressive drugs. This case report underscores the failure of cyclosporin, a treatment not previously reported, to control autoimmunity in antiphospholipid syndrome. Moreover, progressive renal insufficiency can develop as a result of the long-term use of this drug.     

Status of plasmapheresis for the treatment of toxic epidermal necrolysis in Japan

This study describes the efficacy of plasmapheresis for the treatment of toxic epidermal necrolysis (TEN), as reported in Japan. TEN patients treated with plasmapheresis were collected from Japanese literature. The type of plasmapheresis, number of sessions, efficacy of plasmapheresis, and present outcome were examined. Forty-seven TEN patients treated with plasmapheresis have been reported in the literature: 19 men and 28 women with ages ranging from 1 to 96 years (mean 50.3 years). Twenty-five of these treatments included simple plasma exchange (PE), 13 included double filtration plasmapheresis (DFPP), and one included PE and DFPP. The number of plasmapheresis sessions ranged from 1 to 6 and the mean number of sessions was 3.1. The efficacy of plasmapheresis for the treatment of TEN was as follows: excellent, 30 cases; good, 8 cases; fair, 3 cases; no effect, 5 cases; and unknown, 1 case. The rate of effectiveness was 80.9%; eleven patients died; and the mortality rate was 23.4%. In summary, plasmapheresis, including both PE and DFPP, were found to be effective treatments for Japanese patients with TEN, who had been unresponsive to corticosteroids, and for those who show severe clinical manifestations.     

Clinical characteristics,triggering etiologies,and response of plasmapheresis in thrombotic microangiopathy in Taiwan

Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006–2010) and 1352 patients with TMA in the 2011 cohort (2011–2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.     

Interstitial lung disease associated with juvenile dermatomyositis: clinical features and efficacy of cyclosporin A

OBJECTIVES: Interstitial lung disease (ILD) is a rare complication of juvenile dermatomyositis (JDM). The aim of this study was to clarify the clinical features of JDM-associated ILD and to evaluate the efficacy of cyclosporin A (CSA). METHODS: We reviewed clinical records of 10 cases of JDM that were admitted to Hokkaido University Hospital between April 1990 and March 2001. RESULTS: Five cases were complicated with ILD, three with interstitial pneumonia and two with bronchiolitis obliterans organizing pneumonia. ILD was associated with active JDM and progressed despite corticosteroid therapy. Testing for anti-Jo-1 antibody was negative in all cases. Respiratory symptoms were initially noticed in only one case. In the other cases, ILD was first detected by routine examination of chest X-ray. All the cases received CSA (3-5 mg/kg/day) in combination with prednisolone. One patient died of respiratory failure, but the others responded well to treatment with CSA. CONCLUSION: ILD should be evaluated carefully in all cases of JDM regardless of respiratory symptoms. CSA is a choice for steroid-resistant cases of JDM-associated ILD.     

部分羟乙基淀粉代血浆置换治疗血栓性血小板减少性紫癜11例临床研究

目的:对部分羟乙基淀粉代血浆置换技术应用于血栓性血小板减少性紫癜(TTP)进行治疗性研究。方法:进行血浆置换治疗的血栓性血小板减少性紫癜患者共11例,监测治疗前后生化指标的变化情况及转归情况。结果:治疗前后患者的临床症状及生化检查均有不同程度的改善,治疗后患者网织红细胞(Ret)、乳酸脱氢酶(LDH)、血肌酐(Cr)和尿素氮(BUN)与治疗前相比均明显下降(P<0.05),Hb、PLT较治疗前明显上升(P<0.05)。11例患者作血浆置换治疗59次,有效出院者8例,无效出院者1例,死亡1例,经济原因放弃1例,治疗次数2～4次者有效达87.5%。结论:应用部分羟乙基淀粉代血浆加新鲜血浆作为置换液进行血浆置换是治疗TTP患者的有效措施之一,对血浆置换的方法和方式进行研究,有利于减少血浆的使用量、减轻患者的经济负担。     

Management and outcome of pregnancy in autoimmune hepatitis

BACKGROUND: There is a paucity of data in the literature on the risks associated with, and optimal management of, pregnancy in patients with autoimmune hepatitis (AIH). AIMS: To assess maternal and fetal outcomes in relation to clinical management of pregnancy in a large cohort of patients with well defined AIH. METHODS: A review of all known pregnancies in 162 females with definite AIH attending our clinics between 1983 and 1998, with respect to treatment, natural history, and outcome. RESULTS: Thirty one live births (one twin) resulted from 35 pregnancies in 18 women (seven with cirrhosis). Median age at conception was 28 years (range 18-36). Two patients presented with AIH de novo during pregnancy. At conception, in 15 pregnancies patients had been receiving azathioprine alone or (in nine) with prednisolone, in seven prednisolone alone, and in one cyclosporin. Fetal loss at > or =20 weeks' gestation occurred in two instances. Flares in disease activity occurred during four pregnancies and within three months of delivery in a further four. Among the 31 children born (median follow up 10 years) only two abnormalities have been identified: Perthes' disease in one and severe mental and physical handicap in a second who was born prematurely following decompensation of the mother's liver disease. Neither mother was receiving azathioprine. CONCLUSIONS: Successful completion of pregnancy is a realistic expectation for patients with well controlled AIH. Treatment options vary, but azathioprine appears to be generally safe and without adverse outcomes for mother or baby. Vigilance is required, however, and patients need to be monitored carefully during pregnancy and for several months post partum.     

Plasmapheresis for the Treatment of Pemphigus Vulgaris and Bullous Pemphigoid

Abstract: Forty-two cases of pemphigus vulgaris (PV) and bullous pemphigoid (BP) were treated with plasmapheresis by one of 3 techniques: centrifugation, double filtration plasmapheresis (DFPP), or a combination of the two. Each plasmapheresis resulted in a rapid reduction in the autoantibody liter and an improvement in clinical symptoms, thereby allowing a lower dose of corticosteroid to be administered and remission to be achieved. These findings suggest that plasmapheresis is an effective treatment for PV and BP patients who have been unresponsive to conventional therapy, for those for whom conventional drugs are contraindicated due to complications, and for those who show severe clinical manifestations.—     

Cyclosporin for inflammatory pseudotumour.

Dramatic efficacy of cyclosporin was observed in a patient with inflammatory pseudotumour in the liver. The 30-year-old male patient had suffered several attacks of high fever, polyarthralgia and lymph node swelling since 1981. In February 1989, abdominal CT showed multiple space-occupying lesions in his liver, and histopathology of the biopsied liver showed infiltration of plasma cells and lymphocytes with proliferation of collagen fiber, which was comparable to an inflammatory pseudotumour. In May 1990, a treatment regimen of cyclosporin A along with prednisolone was begun because he had been diabetic since March 1990. Within a few days of treatment, the high fever and polyarthralgia subsided, and leucocytosis of 32,000/mm3 and the increased CRP of 17.7 mg/dl were normalised within one month. A reduction of the size of the space-occupying lesions in the liver was observed on abdominal CT taken one month after cyclosporin treatment.     

A case of nonspecific interstitial pneumonia associated with amyopathic dermatomyositis efficiently treated with a combination of cyclosporin A and prednisolone]

A 36-year-old man was admitted to our hospital complaining of cough, dyspnea on exertion, skin eruptions, and joint pain. Characteristic skin lesions such as erythema around the nails, telangiectasis, and edema of the eyelids were observed in this patient. He had never complained of muscle symptoms, and his laboratory examinations showed no elevation of either CPK or aldolase. From several lines of evidence including the skin biopsy findings, amyopathic dermatomyositis was diagnosed. Chest X-ray films showed subpleural funicular opacities and consolidation in both lower lung fields. Lung biopsy specimens taken under video-assisted thoracoscopic surgery revealed nonspecific interstitial pneumonia, group II. Oral prednisolone treatment was initiated at 60 mg daily together with oral cyclosporin A (100-150 mg daily). The minimum serum concentration of cyclosporin A was maintained between 100 and 200 ng/ml. Respiratory symptoms gradually improved, and the oral prednisolone dose was tapered off. Pulmonary function and chest CT findings showed marked improvement.     

Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis

OBJECTIVE: To describe the treatment of polymyositis (PM) and dermatomyositis (DM) with prednisone (PRED) and cyclosporin A (CSA) alone or associated with intravenous immunoglobulin (IVIg) and plasmapheresis (PEX). METHODS: Between 1992 and 1999 CSA and PRED were used to treat 20 patients with idiopathic myositis (12 with DM, eight with PM), diagnosed according to the Bohan and Peter criteria. In patients with refractory or relapsed disease, IVIg was added alone (seven cases) or synchronised with PEX (six cases). A standardised protocol was used to evaluate the patients, and assess disease activity and treatment response. RESULTS: Despite a transient response to PRED and CSA in 16/20 cases, this combination did not induce full remission in 13/20 cases, which led to the IVIg trial with or without PEX. Patients receiving PRED and CSA plus IVIg had a significantly higher probability of maintaining complete remission at the end of the four year follow up period than those treated with PRED and CSA alone (p<0.001). No further benefit was added by the PEX. The presence of arthritis significantly correlated with a poorer response to treatment (p<0.05). Adverse effects were gingival hyperplasia (one patient) and transient renal dysfunction (one). CONCLUSIONS: This open study suggests that combined treatment with PRED, CSA, and IVIg is useful in patients with myositis, even those with refractory or relapsed disease; no increase in the number or type of side effects is seen.     

Diamond-Blackfan Anemia in Japan: Clinical Outcomes of Prednisolone Therapy and Hematopoietic Stem Cell Transplantation

The epidemiology and treatment outcomes for Diamond-Blackfan anemia (DBA) were surveyed in a cohort of 54 children (M/F = 26:28) registered in Japan from 1988 to 1998. The annual incidence was 4.02 cases per million births, the median age at diagnosis was 60 days, and 59% of the cases presented by 3 months of age. Three patients had a familial occurrence. All patients received prednisolone (PSL), and cyclosporin A (CsA) was added to the therapy in 17 patients. Forty-seven patients received transfusions, and 13 underwent hematopoietic stem cell transplantation (HSCT). The cumulative probabilities of a medication-free or a transfusion-free state prior to HSCT were 36% and 69%, respectively, at more than 5 years after diagnosis. Thirteen patients were weaned from PSL therapy without HSCT, and CsA was not associated with weaning from therapy. Transfusion and medication were stopped at 249 days and 933 days after diagnosis in 34 and 13 patients, respectively, who achieved a state of independence. No initial findings predicted the treatment dependence. More than 20% of patients experienced sustained hemosiderosis and/or adverse effects of PSL. The ages and reticulocyte counts at diagnosis of the patients who underwent HSCT were lower than in the patients who did not. HSCT led to the highest success (85%) of all previous reports, even though 5 alternative donors were included in our study. Two cord blood transplants from unrelated donors failed. These findings suggest the need for developing an integral treatment strategy including selective HSCT for refractory DBA.     

Oral cyclosporin in refractory inflammatory bowel disease

Background: The role of cyclosporin in patients with severe, refractory inflammatory bowel disease is unclear. Methods: A seven year retrospective review of patients treated with oral cyclosporin for inflammatory bowel disease refractory to conventional medical therapy was undertaken. Results: Twenty-eight patients (13 ulcerative colitis and 15 Crohn's disease) received oral cyclosporin for a mean of nine months (range 0.25–27 months). Within four weeks of starting cyclosporin, a complete clinical response occurred in 15 patients (nine with ulcerative colitis and six with Crohn's colitis), in whom conventional maintenance treatment was instituted concurrently. The clinical response was sustained during cyclosporin treatment in ten, but maintained after cyclosporin withdrawal in only five patients (18% of entire study group). Four of the five patients who relapsed after cyclosporin withdrawal had failed previously to respond to azathioprine. None of the five patients with continuing remission after cyclosporin withdrawal had received azathioprine in the past. There were three clinically significant infections and 14 cases of impaired renal function during treatment. Conclusions: Oral cyclosporin induces remission in some patients with severe ulcerative colitis or Crohn's colitis, but its benefits in cases refractory to azathioprine are overshadowed by a high frequency of relapse after drug withdrawal. (Aust NZ J Med 1998; 28: 179–183.)     

Final report on a placebo-controlled, double-blind, randomized, multicentre trial of cyclosporin treatment in active chronic Crohn's disease

In a previous report we published the immediate results of a 3-month placebo-controlled trial (n = 34) showing that cyclosporin (n = 37) has a beneficial therapeutic effect in active chronic Crohn's disease. Here we report on the final outcome of the patients. During the 3-month tapering-off period eight initially improved patients (36%) in the cyclosporin group worsened, as did six (55%) in the placebo group. The therapeutic gain of cyclosporin treatment was consistently significant during this period. It ranged from 22% to 25% (95% confidence limits, 2-46%). An outcome ranking showed that 7 patients of the cyclosporin group (19%) were substantially improved, 7 (19%) moderately improved, and 23 (62%) not improved after the tapering off. In contrast, no significant differences were seen during the 6-month follow-up period. Four patients of the cyclosporin group (11%) were substantially improved, 3 (8%) moderately improved, and 30 (81%) not improved at final follow-up. Significant interactions between cyclosporin and prednisolone treatment were demonstrated both at the end of the initial treatment period and at the end of the tapering-off period. We conclude that a short course of cyclosporin treatment does not result in long-term improvement in active chronic Crohn's disease.     

Plasma interleukin-2 and a soluble/shed interleukin-2 receptor in serum of patients with Crohn's disease. Effect of cyclosporin.

Circulating concentrations of interleukin-2 (IL-2) and a soluble or shed form of the IL-2 receptor (sIL-2R) were determined by enzyme-linked immunosorbent assays (ELISA) in 61 patients with chronic active Crohn's disease (CD) initially and during a three month placebo controlled trial of cyclosporin 5-7.5 mg/kg/day. The baseline median (25-75% range) plasma IL-2 concentration was 0.6 ng/ml (0.3-2.85 ng/ml) in patients who did not receive prednisolone, 0.5 ng/ml (0.23-3.4 ng/ml) in patients who did (not significant), and 0 ng/ml (0-0.07 ng/ml) in control subjects (p less than 0.00001). The corresponding median serum sIL-2R concentrations were 747 U/ml (580-1287 U/ml), 540 U/ml (422-616 U/ml) respectively in CD patients (p = 0.006) and 320 U/ml (268-406 U/ml) in control subjects (p less than 0.00001). Increased concentrations of plasma IL-2 and serum sIL-2R were seen in 66% and 81% of the patients, respectively. A fall in serum sIL-2R was only seen in patients who improved with cyclosporin treatment (p = 0.006). At month 3 the median serum sIL-2R concentration was 440 U/ml (400-668 U/ml) v 801 U/ml (534-1067 U/ml) in patients not responding to cyclosporin (p = 0.003). No changes occurred in the placebo group. These results suggest that the IL-2 dependent pathway of immune activation is upregulated in vivo in CD and that cyclosporin may interfere with this process.     

Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia

Immunosuppression with antithymocyte globulin, (methyl)prednisolone, and cyclosporin A is considered the treatment of choice for the patient with aplastic anemia without a donor for standard-risk stem cell transplantation. This consensus is supported by the results of several series, including a randomized German trial. Here we report 11-year results of the latter trial. With stringent response criteria and 4 months as the time to evaluate responses, this analysis confirms the superiority of the cyclosporine regimen regarding the response rate in all patients treated (70% vs 41%, with or without cyclosporine; P =.015) and in patients with severe aplastic anemia (65% vs 31%; P =.011). Patients responded more rapidly after treatment with cyclosporine (median, 60 vs 82 days; P =.019). Most patients treated with cyclosporine needed only one course of immunosuppression, whereas many patients treated without cyclosporine required repeated immunosuppressive treatment. Because of the efficacy of salvage treatment, overall survival was not different between the 2 treatment groups. However, failure-free survival favored the cyclosporine regimen (39% vs 24%; P =.04). The relapse rate, projected at 38% after 11.3 years, was similar between the 2 treatment groups. Remissions were cyclosporine dependent in 26% of the patients responding to a regimen that included cyclosporine. Clonal or malignant diseases developed in 25% of the patients. These data demonstrate that antithymocyte globulin, methylprednisolone, and cyclosporin A are an effective regimen for the treatment of aplastic anemia. However, remissions are unstable, and secondary diseases are common. In contrast to the results of stem cell transplantation, most patients are not cured.     

Successful treatment of acquired factor VIII inhibitor with cyclosporin

Acquired factor VIII inhibitor causes a rare but life-threatening form of bleeding disorder, owing to the formation of auto-antibodies against FVIII. Treatment modalities include the use of immunosuppressive drugs such as cyclophosphamide and corticosteroids, plasmapheresis and i.v. immunoglobulin. A patient with idiopathic acquired FVIII inhibitor presented with serious bleeding complications resistant to all the above therapeutic modalities. Treatment with cyclosporin, however, resulted in a prompt and complete response. The lack of side-effects and the relatively quick response suggest that cyclosporin may be tried as front line treatment for patients with acquired FVIII inhibitors.