Elisa Stipa

Long-Term observation of 208 adults with chronic idiopathic thrombocytopenic purpura**

PURPOSE To define response to therapy and ultimate outcome of adults with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS We retrospectively analyzed patients with ITP diagnosed between 1978 and 1988, and reexamined them between June 1992 and March 1993. Data from 208 cases were collected. Median patient age was 44 years (range 14 to 78) at the time of diagnosis, and 51 years (range 19 to 86) at reexamination. Length of follow-up ranged from 48 to 151 months (median 92) and was longer than 10 years in 26 patients (12.5%). Reexamination included a careful interview, physical examination, complete blood count, screening for HIV infection, determination of platelet-bound IgG, and, in persistently thrombocytopenic patients, autoimmunity markers and routine laboratory investigations. RESULTS A total of 121 patients with fewer than 50 x 10(9) platelets per liter received an initial treatment with prednisone (PDN) at a dosage of 1 mg/kg of body weight for 1 month. Refractory or relapsed cases underwent splenectomy and/or other therapeutic modalities. In 87 patients with greater than 50 x 10(9) platelets per liter, no therapy was scheduled. An initial complete response to PDN was observed in 38.8% cases. A sustained complete remission (CR) lasting more than 6 months with no maintenance therapy was attained in 18.7%. At the time of last follow-up only 11 of these patients remained in CR. Sixty-three patients underwent splenectomy. Forty-seven (74.6%) had a CR, with 41 achieving a prolonged recovery (> 6 months). Twelve other cases attained a sustained partial remission. Long-lasting recoveries were observed in 7 other cases following alternative treatments. Spontaneous remissions occurred in 8 of 87 untreated cases after observation periods of 6 months or more. Eleven deaths were recorded (6 women and 5 men, median age 73), but only 5 were attributable to thrombocytopenia. At last control, 43 patients were in complete remission and free from therapy, and 52 were still on therapy. Four thrombocytopenic patients had laboratory features and a clinical history consistent with an autoimmune disease. CONCLUSIONS This analysis of ITP in adults suggests that splenectomy remains the most effective treatment. The majority of patients who undergo splenectomy can have a CR for many years, while only a minority of those who do not have this therapeutic modality or fail it are likely to attain similar results. The long-term prognosis of ITP is benign even in refractory cases. Spontaneous remissions can be observed in a significant percentage of untreated patients (about 9%). The development of overt autoimmune diseases is relatively uncommon. Particular attention should be given to the management of ITP in the elderly, where bleeding episodes of the central nervous system tend to occur more frequently.

Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell–depleting therapy with rituximab

The effects of B-cell depletion with rituximab on regulatory T cells (Tregs) have not been determined. We investigated Tregs in patients receiving rituximab for chronic idiopathic thrombocytopenic purpura (ITP). The peripheral blood Tregs, identified as CD4+FOXP3+ T cells, were measured by flow cytometry prior to and after the immunotherapy. In addition, Tregs were analyzed for their usage of the T-cell receptor (TCR) beta-variable (VB) region gene as well as their regulatory function as assessed by cell proliferation assays. Pretreatment data revealed a reduced number and a defective suppressive capacity of Tregs in ITP patients compared with control individuals. In addition, Tregs showed a polyclonal spectratype. Patients, particularly responders, showed restored numbers of Tregs as well as a restored regulatory function upon treatment with rituximab. These results indicate that patients with active ITP have a defective T regulatory cell compartment that can be modulated by a B cell-targeted therapy.

Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management.

Idiopathic thrombocytopenic purpura (ITP) is characterized by a low platelet count, which is the result of both increased platelet destruction and insufficient platelet production. Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP, several abnormalities involving the cellular mechanisms of immune modulation have been identified. Conventional treatments for ITP aim at reducing platelet destruction, either by immunosuppression or splenectomy. Two new thrombopoietic agents, AMG 531 and eltrombopag, have been used in clinical trials to stimulate platelet production in ITP patients not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin, but still bind and activate the thrombopoietin receptor. This review will focus on the pathophysiology and treatment of ITP in adults, highlighting recent advances in both fields.