FIFTY YEARS O F I DIOPATHIC T HROMBOCYTOPENIC P URPURA ( ITP): MANAGEMENT OF R EFRACTORY I TP IN ADULTS

Autoimmune disorders, in which there is loss of tolerance toself antigens, affects 5% of the population representing14 million individuals in the USA and 3 million in the UK(Editorial, 2001). To date, the treatment of these disordersin adults has been disappointing, in part because of a lack ofunderstanding of the underlying pathophysiology in thisdiverse group of disorders.Some 50 years ago, Harrington et al (1951) elegantlydemonstrated the presence of a factor in the globulinfraction in the peripheral blood of patients with idiopathicthrombocytopenic purpura (ITP) that caused the thromb-ocytopenia. We now know that this factor was anti-plateletantibody. However, despite major advances in our under-standing of immunology and autoimmunity, these have notbeen translated into improved diagnostic or therapeuticstrategies for diseases such as ITP. Although severaldifferent classes of drug and other forms of treatment havebeen used in chronic ITP, no therapeutic modality is trulyevidence based (George et al, 1996).In our opinion, ITP represents an ideal model of organ-specific autoimmune disease for study. It is sufficientlycommon to make its study feasible and has the advantage ofbeing manifested by a reduced peripheral blood plateletcount. As such, the efficacy of treatment can be objectivelymeasured by using the full blood count. In this article, welook at how far we have moved on since Harrington’sseminal work and define the disorder, discuss the underly-ing immunological features, summarize the standard ther-apy and evaluate the treatments available for non-pregnantadults who are refractory to standard first-line therapy. Wehave also reviewed therapies under development thatappear to offer a more targeted approach to treatment.Using ITP as a model of human autoimmune disease couldlogically lead to improvements in the management of morecomplex disorders such as multiple sclerosis, systemic lupuserythematosus (SLE) and type I diabetes mellitus.HOW HAS THE DIAGNOSIS AND MANAGEMENTOFITPADVANCEDINTHELAST50YEARS?Disease definitionIdiopathic thrombocytopenic purpura (ITP) is an auto-immune disorder in which platelets, opsonized withanti-platelet autoantibodies, are removed prematurely bythe reticuloendothelial system (RES), leading to a reducedperipheral blood platelet count. Although bone marrowmegakaryocytes are often increased, relative marrow failuremay play a role in a proportion of patients (Ballem et al,1987). The aetiology of ITP in adults is unknown and theclinical course is variable and unpredictable.The incidence of chronic adult ITP is around 5AE8–6AE6 newcases per 100,000 population per year in the USA (Bottiger& Westerholm, 1972; McMillan, 1997), and a similarincidence in the UK. The overall combined incidence of newcases of adult and childhood ITP is higher, and may reach20 per 100,000 population per year.The pathogenesis (and treatment) of ITP has beenreviewed by several authors (Berchtold & McMillan, 1989;Chong, 1995; Ikehara et al, 1995; Semple & Freedman,1995; Karpatkin, 1997; Wang & Shen, 1997; Blanchetteet al, 1998; Yang & Zhong, 2000; Lechner, 2001).ITP in childhood is generally termed acute as the illnessis seasonal, typically follows a trivial viral infection orvaccination, and in most cases is transient, requiresno treatment and spontaneously recovers. In the adult(chronic) form there is usually no obvious antecedent illnessand most patients have chronic thrombocytopenia; sponta-neous recovery is uncommon (George et al, 1996). Inadults, the frequency of death from haemorrhage in patientsfailing to achieve an adequate platelet count is 5% (Georgeet al, 1996), although the frequency may be influenced byage and duration of thrombocytopenia (Frederiksen &Schmidt, 1999).Clinical featuresThe ITP phenotype is heterogeneous: some patients suffermajor bleeding from the outset, while others have fewproblems apart from an increased bruising tendency. Thismay partly be explained by the acquired platelet dysfunctionwhich is seen in some patients with ITP, which in turn maybe related to the target antigen involved in the autoimmuneprocess (this is discussed later in Autoantibody characteris-tics). Autoantibodies reacting with glycoprotein (GP)IIb ⁄IIIa affect platelet aggregation and anti-GPIb ⁄IX autoan-tibodies impair platelet adhesion to the subendothelialmatrix, causing unexpectedly severe bleeding for the levelof the platelet count (Wang & Shen, 1997). In general,however, in contrast with thrombocytopenia due to marrowinfiltration (e.g. leukaemias, lymphomas or other malig-nancies) or aplasia, patients with ITP are able to tolerateremarkably low platelet counts and maintain an adequatequality of life (Karpatkin, 1985). The degree of bleeding islargely dependent on the platelet count and patients with