Immunosuppressive therapy Corticosteroids Corticosteroids (CS) were the ﬁrst immunosuppressive drugs used in the treatment of PRCA and so far have been considered the treatment of ﬁrst choice, especially in young adults (Clark et al, 1984; Dessypris, 1988; Charles et al, 1996; Dessypris & Lipton, 2004). The details of CS therapy are described elsewhere (Dessypris, 1988; Dessypris & Lipton, 2004). In an era when CsA was not yet available, Clark et al (1984) reported the largest series of PRCA patients receiving immunosuppressive therapy and showed that 10/27 (37%) patients with acquired PRCA responded to CS within a mean period of 2Æ5 weeks. Compa- rable results of CS treatment were obtained at other institu- tions, ranging from 30–62% (Dessypris, 1988; Raghavachar, 1990; Marmont, 1991; Lacy et al, 1996; Mamiya et al, 1997). One of the important drawbacks of CS is that relapse is not uncommon: 80% of patients relapsed, as the dosage was tapered, during the 24 months after remission (Clark et al, 1984). The principal reason for discontinuing the drug, despite subsequent recurrence of anaemia, was the presence of unacceptable side effects, such as myopathy, infection, hyper- glycemia, and compression fractures at the dose required to maintain remission. Treatment of relapses was successful, with 10/13 (77%) patients entering a second or third remission, and the median survival in patients with primary idiopathic PRCA was 14 years (Clark et al, 1984). Cytotoxic drugs administered in combination with CS were the most effective form of treatment in this study, producing 18/32 (56%) remissions. Although such vigorous immunosuppressive treatment is capable of inducing and maintaining remission in a majority of patients, it carries increased risks of serious infections, malignancy, and sterility (Clark et al, 1984). Thus, an individ- ualized approach to management of PRCA has been widely accepted, i.e. escalating therapy in proportion to the severity of the disease for those patients who have failed CS therapy. Cyclosporin A Raghavachar (1990) reviewed the treatment of PRCA, focusing on the results of cyclosporin A (CsA) therapy, in 43 patients. He showed that the overall response rate to CsA is excellent (65%) and proposed that CsA should be the ﬁrst drug to be given in acquired PRCA. Of note is that a high dosage was used in order to obtain these results (12 mg/kg per day). Compa- rable results of CsA treatment have been obtained at other institutions, ranging from 65–87% (Dessypris, 1988; Marmont, 1991; Means et al, 1991; Lacy et al, 1996; Mamiya et al, 1997; Sawada et al, 2007). Mamiya et al (1997) reviewed the clinical features of 150 patients with acquired PRCA in Japan. In their surveillance, CsA was given to 38 patients in a daily dose of 200–600 mg (most often 200–300 mg) and 31 (82%) showed haematological recovery. The response rate to CsA was 87% in the patients with primary PRCA and 73% in those with Review secondary PRCA, which encouraged them to recommend CsA therapy as ﬁrst-line therapy for this disease. Recently, The Japan PRCA Collaborative Study Group conducted a nationwide survey in Japan between 1990 and 2006 (Sawada et al, 2007). From a total of 185 patients, consisting of 73 primary idiopathic and 112 secondary PRCA cases, 62 patients with primary idiopathic PRCA were evalu- ated, which is the largest and the longest follow-up study so far. Although a retrospective one, this study, for the ﬁrst time, answered many of the unknown questions concerning CsA therapy. The remission induction therapies for these patients by CsA and CS produced remissions in 74% and 60% of patients, respectively. The initial dose of CsA for the respond- ing patients was 4Æ8 ± 1Æ2 mg/kg (mean ± SD, n = 23) with a range of 2Æ9–7Æ6 mg/kg body weight. Patients treated with CsA alone (n = 23) became transfusion-independent by 82 ± 200 d, with a range up to 910 d, after the start of therapy. Fifteen patients (65%) achieved transfusion-indepen- dence within 2 weeks, 17 patients (74%) within 1 month and 18 patients (78%) within 3 months. Salvage immunosuppres- sive treatment achieved remissions in 58 patients (94%). Forty-one and 15 patients were maintained on CsA ± CS (CsA-containing group) or CS alone (CS-group), respectively. The median relapse-free survival (RFS; estimated as trans- fusion-free survival) in the CsA-containing group was 103 months, signiﬁcantly longer (P < 0Æ01) than that seen in the CS-group (33 months). Thus, combined CsA therapy can sustain a longer duration of initial remission than CS, however, discontinuation of maintenance therapy was strongly corre- lated with relapse (P < 0Æ001) and caused relapses with a median of 3 months with a range of 1Æ5–40 months. In contrast, 88% of relapses in the CS-group occurred during maintenance prednisolone (PSL) therapy (Sawada et al, 2007). To¨tterman et al (1989) also reported that PRCA patients did not remain in remission after CsA was stopped. An important question is whether or not the maintenance of patients in remission may have a beneﬁcial inﬂuence on survival. One study (Sawada et al, 2007) reported an estimated median OS of the CsA-containing group of 12 years, which was not signif- icantly different than the CS-group, while the 10-year OS in all patients was 95% and the median OS had not yet been reached in all patients. Of importance is the fact that the CsA is required to maintain remissions (Sawada et al, 2007) and the decreased probability of relapse and requirement of red cell transfusions reduces the dangers of hemolysis, infections and iron overload with possible superoxide damage to body tissues. CsA is more expensive than CS and requires renal function to be monitored, but it seems to be important to prevent relapses and to sustain remissions in primary idiopathic PRCA. Although higher doses of CsA, such as 12 mg/kg per day have been used for patients with PRCA (Raghavachar, 1990), this dosage has been toxic for Japanese PRCA patients. Since cytochrome P-450 isoenzymes, involved in CsA metabolism, have a variable frequency of a reduced function allele depending on race and each individual (Bladford, 2004), the ª 2008 The Authors Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 142, 505–514 507