Human immunodeficiency virus-associated thrombotic microangiopathies: clinical characteristics and outcome according to ADAMTS13 activity.

Human immunodeficiency virus (HIV) infection is a risk factor for thrombotic microangiopathy (TMA). We sought whether a severe deficiency in ADAMTS13, the enzyme specifically involved in the cleavage of von Willebrand factor, was associated with specific presenting features and outcome in HIV-associated TMA. In this prospective, multicentre, case-control study, 29 patients of 236 in the French Network on TMA had an HIV-associated TMA. Seventeen patients with severe ADAMTS13 deficiency (ADAMTS13 <5% HIV(+) group) were compared to 12 patients with a detectable ADAMTS13 activity (ADAMTS13 >or=5% HIV(+) group). HIV(+) patients were also compared to 62 patients with idiopathic TMA, either with (45 patients, ADAMTS13 <5% idiopathic group) or without (17 patients, ADAMTS13 >or=5% idiopathic group) severe ADAMTS13 deficiency. ADAMTS13 <5% HIV(+) patients had less AIDS-related complications than ADAMTS13 >or=5% HIV(+) patients (23.5% versus 91.6%, respectively, P = 0.0005) and their median CD4(+) T cell count was higher (P = 0.05). TMA-associated death rate was higher in ADAMTS13 >or=5% HIV(+) patients than in ADAMTS13 <5% HIV(+) patients (50% versus 11.7%, respectively, P = 0.04). In ADAMTS13 <5% patients, TMA-associated death rate was comparable between HIV(+) and idiopathic patients (15.5% in idiopathic patients, P-value was non-significant). By contrast, TMA-associated death rate in ADAMTS13 >or=5% HIV(+) patients was higher than in idiopathic patients (11.7% in idiopathic patients, P = 0.04). In conclusion, HIV-associated TMA with severe ADAMTS13 deficiency have less AIDS-related complications and a higher CD4(+) T cell count. TMA prognosis is better and comparable to this of idiopathic forms.

Human fear-related motor neurocircuitry.

Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans.

Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases.

BACKGROUND: Case reports have suggested that extracorporeal photochemotherapy (ECP) might be beneficial for the treatment of erosive oral lichen planus (OLP) recalcitrant to conventional immunosuppressive therapies. OBJECTIVES: To evaluate over a long-term period the clinical efficacy and toxicity of ECP in a series of patients with refractory OLP, and to monitor peripheral blood lymphocyte subset counts under treatment. METHODS: Twelve patients with refractory OLP underwent a standardized protocol of ECP. Sessions were performed twice weekly for 3 weeks, and then the treatment schedule was adapted according to clinical benefit. The disease severity was evaluated monthly on a clinical basis. Complete remission was defined as the absence of any erosion and partial remission as a decrease of at least 50% of erosion surface. Blood cell counts with CD4+ and CD8+ lymphocyte subsets were evaluated every 3 months. RESULTS: All patients showed a decrease of the erosive surface; nine (75%) achieved a complete remission and three (25%) a partial remission. Seven of the eight patients followed for more than 3 years had recurrences of erosions when ECP sessions became less frequent or were stopped. After resumption of an initially accelerated regimen of ECP, all again showed partial or complete remission. Blood lymphocyte counts decreased during treatment, without statistically significant changes in CD4+/CD8+ ratio, and increased during relapse. CONCLUSIONS: ECP is an effective alternative therapy in erosive OLP showing resistance to classical treatments. The decrease in blood lymphocyte counts appears to parallel the clinical improvement under treatment.

Prognostic value of inhibitory anti-ADAMTS13 antibodies in adult-acquired thrombotic thrombocytopenic purpura.

In order to assess the prognostic value of inhibitory anti-ADAMTS13 antibodies in thrombotic thrombocytopenic purpura (TTP), we performed a multicentre prospective study of 33 adult patients with idiopathic acquired TTP. Patients were treated with high-dose plasma infusion and therapeutic plasma exchange. Patients without (group 1, n = 12) and with (group 2, n = 21) detectable inhibitory anti-ADAMTS13 antibodies were compared for clinical presentation, treatment and outcome. Both groups were comparable for clinical presentation. All patients in group 1 achieved a sustained complete remission within a median of 7 d [95% confidence interval (CI), 4-18], which required a median plasma volume of 235 ml/kg (range, 131-1251). In group 2, 17 patients achieved a durable complete remission within a median of 23 d (95% CI, 11-32) (P = 0.001). Median plasma volume was 718 ml/kg (range, 219-3107) (P = 0.02). In group 2, there was a trend for more episodes of flare-up than in group 1 (13 vs. 3, respectively, P = 0.07). Four patients, all from group 2, died (P = not significant). The relapse rate was comparable between both groups. We suggest that TTP with detectable inhibitory anti-ADAMTS13 antibodies displays a worse prognosis, relative to a delayed platelet count recovery, a higher plasma volume requirement to achieve complete remission, and a trend for more frequent episodes of flare-up.

Effectiveness of platelet transfusions after plasma exchange in adult thrombotic thrombocytopenic purpura: a report of two cases.

Plasma infusion (PI) and plasma exchange (PE) are the most efficient treatment of thrombotic thrombocytopenic purpura (TTP), allowing achievement of complete remission in 60 to 90% of cases. Life-threatening bleeding, related to severe thrombocytopenia, is one of the main complications of the disease. Thrombocytopenia may also preclude invasive procedures such as splenectomy, which may be required during the management of TTP. Platelet concentrates transfusions are usually thought to worsen the disease, especially if not associated with the appropriate treatment of this latter, and thus should be avoided. We report hereon 2 patients with TTP who experienced a surgical procedure i.e., a cholecystectomy for a cholecystitis, and a splenectomy for a refractory TTP. In both patients, the surgical procedure was preceded by a 60 mL/kg plasma exchange with solvent/detergent treated plasma as replacement fluid, followed by platelet transfusion, with a corrected count increment of 57.1% (Patient 1) and 69.3% (Patient 2). Using this sequential treatment, the patients did not experience any deterioration of their status. Both patients had a favorable outcome after surgery. However, until such a procedure will be validated on a larger series of patients, it should be restricted to patients presenting with a refractory life-threatening thrombocytopenia and/or requiring surgery or any kind of invasive procedure. Am. J. Hematol. 68:198-201, 2001. Published 2001 Wiley-Liss, Inc.

Indications of plasma exchanges in 2000.

In Hematology, Neurology, in renal diseases, and autoimmune diseases.

[Resistant acquired bullous epidermolysis with severe ocular involvement: the success of extracorporeal photochemotherapy]. / Epidermolyse bulleuse acquise résistante avec atteinte oculaire sévère: succès de la photochimiothérapie extracorporelle.

BACKGROUND: Epidermolysis bullosa aquisista can leave several functional sequelae. The lesions sometimes resist treatment. CASE REPORT: We report a case of a 25-year-old young man presenting with a severe epidermolysis bullosa acquisita confirmed by the electronic immunomicroscopy. He had a major ocular involvement with symblepharon and cicatricial synechial lesions. He was almost blind because of corneal scars. All immunosuppressive treatments had failed: systemic corticoids, cyclosporin, azathioprine. The introduction of extracorporeal photochemotherapy resulted in the healing of the lesions, after a total of 32 procedures. All treatment are now stopped, and the lesions are purely cicatricial, without any relapse of the disease since 9 months. Corneal grafts are now under process, to try to recover a part of the lost visual acuity. DISCUSSION: This case demonstrates the efficacy of extracorporeal chemotherapy to be tried in case other treatments failed.

Circulating malignant lymphocytes from Sezary syndrome express high level of glycoproteins carrying beta (1-6)N-acetylglucosamine-branched N-linked oligosaccharides.

The circulating forms of malignant cells from patients with Sezary syndrome exhibit on their glycoproteins a high level of beta (1-6)GlcNAc-branched N-linked oligosaccharides, a particular species of glycans related to the metastatic potential of several tumors and T lymphocytes activation. An increased activity of the N-acetylglucosaminyltransferase V and of the beta (1-4)galactosyltransferase, two enzymes implicated in beta (1-6)GlcNAc-branching is also found. Nevertheless, contrary to activated normal T lymphocytes, Sezary lymphocytes in agreement with their non-proliferating state, do not exhibit increased thymidine uptake. This result suggests that expression of the beta (1-6)GlcNAc-branched N-linked carbohydrates could be related to some of the malignant properties of Sezary lymphocytes.

p53 antibodies in patients with various types of cancer: assay, identification, and characterization.

Alteration of the p53 gene is the most frequent genetic alteration in human cancer and leads to the accumulation of mutant p53 in the nucleus of tumor cells. In addition, it has been shown that patients with various types of neoplasia have p53 antibodies in their sera which could be used as an indirect diagnostic procedure for p53 alteration. Using a new ELISA, we have analyzed the sera from more than 1000 patients with various types of cancer and from healthy blood donors. We demonstrate that p53 antibodies are detected mainly in cancer patients and are strictly proportional to the occurrence of p53 mutations. Using various immunological approaches, these antibodies were unambiguously demonstrated to be directed toward the human p53 protein. Isotyping analysis of these antibodies strongly suggested that they correspond to a humoral response to the p53 protein which accumulates in the tumor cell. This finding suggests that serological analysis, combined with histochemistry, is suitable for assessing the integrity of the p53 gene in cancer patients.

Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome patients with factors predicting poor prognosis. A prospective, randomized trial in sixty-two patients.

OBJECTIVE: To define the most effective treatment for severe polyarteritis nodosa (PAN) and Churg-Strauss syndrome (CSS) and to investigate the indication for plasma exchange treatment. METHODS: We conducted a prospective, randomized, multicenter trial in which 62 patients were randomly assigned to receive either prednisone plus cyclophosphamide (intravenous bolus) (group A; n = 28) or prednisone plus cyclophosphamide (intravenous bolus) plus plasma exchanges (group B; n = 34) as first-line treatment for severe PAN or CSS. Factors predicting poor prognosis were renal symptoms, gastrointestinal tract involvement, cardiomyopathy, central nervous system involvement, weight loss > 10% of body weight, and age > 50 years old. Patients with hepatitis B virus-related PAN were not included in this study. The end point of the study was control of the disease (recovery or remission) or death. RESULTS: Clinical symptoms and laboratory findings did not differ significantly in the 2 groups. Initial control of the disease was similar in both groups. Relapse after initial control of the disease was observed in 7 patients (4 in group A and 3 in group B). The mean +/- SD followup period was 31.1 +/- 20 months for group A and 35.9 +/- 16.8 months for group B. At 5 years of followup, 38 patients (61.3%) were cured (16 in group A and 22 in group B), and 5 (8.1%) were in remission without treatment but had not yet completed the cure-defining period of 18 months (3 in group A and 2 in group B). Eight (12.9%) (2 in group A and 2 in group B) were considered to be in clinical remission and required a maintenance regimen of low-dose corticosteroids. Eleven patients died during the study period (7 in group A [25%], 4 in group B [11.8%]). Uncontrolled vasculitis was responsible for 4 deaths (2 in each group), and treatment side effects caused the death of 1 patient in group A. There was no significant difference between the 5-year cumulative survival rates of the 2 groups (75% and 88%, respectively). CONCLUSION: Based on our data, combined treatment with prednisone, cyclophosphamide, and plasma exchanges is not superior to treatment with prednisone and cyclophosphamide alone, and plasma exchanges should not be systematically proposed for initial treatment of severe PAN or CSS.

International forum: France. The national survey of plasma exchange and therapeutic cytapheresis in France.

Created in 1985, the French Society of Haemapheresis (SFH) Registry is the largest data base of plasma exchange (PE) in the world. Data analysis shows that neurological diseases are the most frequent indications for PE in France and that improvement in technique has reduced early complications. As for therapeutic cytapheresis, peripheral blood stem collection represents the major activity (64%). The second most common activity is UVA extracorporeal photochemotherapy.

Plasma exchange and chlorambucil in polyneuropathy associated with monoclonal IgM gammopathy. IgM-associated Polyneuropathy Study Group.

The study compared chlorambucil alone with chlorambucil in combination with plasma exchange in patients with polyneuropathy associated with monoclonal IgM. Forty four patients were prospectively randomly assigned, in a comparative open trial, to receive either 0.1 mg/kg/day chlorambucil orally, for 12 months or chlorambucil associated with 15 courses of plasma exchange, during the first four months of treatment. They were evaluated by a neuropathy disability score and nerve conduction studies. No difference was found between the two treatment groups. The average neuropathy disability score improved by 2.1 points from baseline (21.0 to 18.9) in the chlorambucil group and by 1.8 points (20.4 to 18.6) in the chlorambucil + plasma exchange group (P = 0.70). The mean motor nerve conduction velocity decreased from 20.0 to 18.2 m/s in the chlorambucil group and increased from 20.5 to 22.5 m/s in the chlorambucil + plasma exchange group (P = 0.51). A slight improvement of the sensory component of the neuropathy disability score (from 10.5 to 8.3) was noted in both groups (P = 0.01). At the end of the study and according to self evaluation, 15 patients--eight from the chlorambucil group and seven from the chlorambucil + plasma exchange group--reported clinical improvement, whereas 15--eight from the chlorambucil group and seven from the chlorambucil + plasma exchange group--reported clinical worsening. Neuropathy remained stable in the others. Thus plasma exchange seemed to confer no additional benefit in the treatment of polyneuropathy associated with monoclonal IgM.

[Development of indications and techniques of plasma exchange. Contribution of the French Registry of Hemapheresis. Group Coopératif Français]. / Evolution des indications et techniques des échanges plasmatiques. Les enseignements du Registre Français d'Hémaphérèse. Group Coopératif Français.

The French Registry for Haemapheresis created in 1985 allows an analysis of the changing indications and techniques of plasma exchange. The data collection system has been improved since 1991 with the development of a telematic network which greatly shortens the delay to data analysis. The 8-year report shows an increase in the use of the centrifugation technique, with citrate anticoagulation alone, a very sharp decline in the use of plasma substitution with albumin alone largely replaced by combined albumin, and no change in vascular access. Indications are now dominated by the constant increase in the use of plasma exchange for neurological diseases, a relative stability in the field of haematology and a drop in the number of indications for connective tissue diseases and nephrology. Advances in the technique have led to a decline in complications observed earlier. The French Registry for Haemapheresis is the world's largest data base on plasma phoresis. Participation via telematic access is essential for further extension of the registry.

[Managing of an innovation in health care: the case of polyvalent intravenous immunoglobulins at the Assistance-Publique-Hôpitaux de Paris]. / La maîtrise de la diffusion d'une innovation en Santé: le cas des immunoglobulines intraveineuses polyvalentes à l'Assistance Publique-Hôpitaux de Paris.

Managing new innovations in medicine is a particularly timely subject. There is an abundant history concerning over expectations resulting from the development of new treatments or diagnostic procedures, some shown to be less effective than promised, others even found to be dangerous. A new aspect to the question is the importance of economic pressures which require rational investment decisions when diffusing innovating technologies. In 1991, the Commission for the evaluation and diffusion of innovating technologies (CEDIT) at the University Hospitals of Paris (Assistance Publique-Hôpitaux de Paris) developed a programme aimed at better managing the distribution and use of polyvalent intravenous immunoglobulins (IgIV), a new promising therapeutic tool with both a high cost and a certain number of risks. The programme was designed to assist prescribers in elaborating better therapeutic strategies and to help hospital managers rationalize expenditures for IgIV. The results of this experience are presented here together with certain conclusions concerning the way management decisions can be applied to the diffusion of an innovation in health care.

Treatment of Crohn's disease by lymphocyte apheresis: a randomized controlled trial. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives.

BACKGROUND/AIMS: Several uncontrolled trials suggest that lymphapheresis improves the clinical course of patients with Crohn's disease; this study was designed to assess the efficacy of lymphapheresis in preventing early relapses of Crohn's disease in patients in clinical remission after steroid treatment for an acute attack. METHODS: Twenty-eight patients in clinical remission at the end of 3-7 weeks of steroid therapy were included in this randomized multicenter prospective trial. Before starting steroid tapering, patients were randomly assigned either to the lymphapheresis group (9 procedures within 4-5 weeks) or to the control group. The primary judgement criterion was the cumulated recurrence rate after steroid discontinuation. RESULTS: All the patients treated by lymphapheresis (12 of 12) were successfully withdrawn from prednisolone and only 10 of 15 in the control group (NS). At the end of the 18-month follow-up period, the cumulated relapse rate was 83% in the lymphapheresis group and 62% in the control group. CONCLUSIONS: Although there was a trend towards a diminished incidence of corticosteroid dependence, lymphapheresis did not prevent the occurrence of early relapses.

Long-term plasma exchange. Analysis of indications, outcome and side effects.

In order to determine the characteristics and the course of diseases treated with long-term plasmapheresis (e.g., more than 25 plasma exchanges), we retrospectively studied 850 patients who underwent plasmapheresis. Long-term plasma exchange was prescribed to 38 patients who failed to respond to conventional therapy; cryoglobulinemias, peripheral neuropathies and monoclonal gammopathies were their most frequent underlying diseases. Improvement was noted in 65.8% cases. Only minor side effects were observed and the risk/benefit ratio for such therapy was excellent.