© Springer Nature Singapore Pte Ltd. 2017
Yoji Ishida and Yoshiaki Tomiyama (eds.)Autoimmune Thrombocytopenia 10.1007/978-981-10-4142-6_13Steroids
(1)
Department of Clinical Research, Hiroshima-Nishi Medical Center, Hiroshima, Japan
(2)
Department of Nursing, Yasuda Women’s University, Hiroshima, Japan
Abstract
Since the 1950s, corticosteroids, particularly prednisolone, have been key drugs in the initial treatment of immune thrombocytopenia (ITP). However, issues are associated with the long-term efficacy of prednisolone and its side effects in patients treated for a long period of time. Since the 1990s, HD-DEX has attracted attention because of its faster response, shorter treatment period, higher efficacy rate, and tolerability. A number of trials have recently been performed in order to improve the initial treatment of ITP.
1 Introduction
Immune thrombocytopenia (ITP) is mediated by autoantibodies against platelet-specific antigens including the GPIIb/IIIa and GPIb-IX-V complexes. Platelets coated with autoantibodies are captured and cleared by tissue macrophages through Fcγ receptors in the reticuloendothelial system, which includes the spleen and liver. Macrophages also function as antigen-presenting cells that interact with T cells, which, in turn, activate antibody-producing B cells. Antiplatelet autoantibody production is maintained by this pathogenic loop [1, 2]. Cytotoxic T cells directly affect platelets and megakaryocytes and contribute to the diverse pathobiology of ITP [3, 4].
Since the 1950s, corticosteroids have been used as a key drug to treat ITP and are still the mainstay of treatment for ITP [5]. Treatments using corticosteroids prevent the destruction of autoantibody-coated platelets in the reticuloendothelial system. Corticosteroids have also been reported to impair autoantibody production because they decrease platelet-associated IgG levels [1]. Corticosteroids may also increase the production of platelets from megakaryocytes by impairing the ability of macrophages and cytotoxic T cells to destroy platelets within bone marrow [2]. Additionally, they may also have a direct effect on blood vessels and reduce bleeding independent of increases in the platelet count [6, 7]. However, the adverse effects of corticosteroids have become apparent and create significant complications. The deleterious effects of corticosteroids often exceed their benefits.
In this chapter, we review the use of each corticosteroid in the treatment of ITP and reconsider strategies for the management of ITP patients.
2 Prednisolone (Prednisone)
Prednisolone and prednisone are both artificially synthesized corticosteroids that are used in the treatment of various diseases including inflammatory disorders, autoimmune diseases, and lymphoid malignancies. Prednisone is activated to prednisolone in the liver. Only prednisolone is approved in Japan.
George et al. reviewed the clinical course of adult ITP in 12 case series of 1761 adults between 1928 and 1989. Since the 1950s, most adults have been promptly treated with glucocorticoids, and approximately 25% of all patients treated with glucocorticoids may achieve a complete response [5].
Based on these findings, George et al. proposed glucocorticoid therapy in the initial management of a newly diagnosed ITP patient [5]. Although they indicated that patients with asymptomatic mild or moderate thrombocytopenia may be followed with no treatment, oral prednisone (1 mg/kg/day) was recommended as conventional initial therapy for newly diagnosed patients with more severe thrombocytopenia. Similar initial therapy has since been recommended by other reviews [1, 2].
In 1996, George et al. published practical guidelines for ITP developed by explicit methods for the American Society of Hematology [8]. Other guidelines were subsequently published by various medical societies [8–11]. These guidelines also recommend the use of oral corticosteroids in the initial treatment.
In 2012, a panel for Blood Coagulation Abnormalities in Japan belonging to the Ministry of Health, Labour and Welfare of Japan published a reference guide for the management of adult ITP [12]. Although the reference guide also recommends the use of oral prednisolone as the first-line treatment, similar to the other guidelines, it provides considerations prior to the initiation of treatment. Patient backgrounds, including hypertension, diabetes, active infections, osteoporosis, hyperglycemia, immune suppressive states, and peptic ulcers, need to be considered. The aggravation of these complications and occurrence of unexpected adverse events also need to be taken into account. The recommended dosage of prednisolone is 0.5–1.0 mg/kg/day for 2–4 weeks. In patients with various complications and older patients, the reference guide recommends a starting dose of 0.5 mg/kg/day prednisolone. Even if platelet counts do not increase, the daily dose is slowly tapered to the maintenance dose (less than 10 mg/body/day). If the bleeding tendency deteriorates during the tapering or cessation of prednisolone, increasing the dose administered, the reinitiation of prednisolone, or the initiation of other treatments including intravenous immunoglobulin (IVIG) needs to be considered. The efficacy of oral corticosteroids is noted as follows: the platelet count starts to increase 3–4 days after starting the treatment, and, in rare cases, a response is not observed for 1 week or longer. Response rates range between 50 and more than 75%, depending on the intensity and duration of therapy. The incidence of continuous remission ranges is between 10 and 20% [13, 14]. If initial treatment using corticosteroids is ineffective, a bone marrow examination needs to be planned in consideration of other disorders such as myelodysplastic syndrome.
3 Methylprednisolone
An immediate intervention in the platelet count may be required for some patients needing surgical procedures or active central nervous system, gastrointestinal tract, urological, or gynecological bleeding. Many reviews and guidelines note that emergent treatment needs to include IVIG, high-dose intravenous methylprednisolone (mPSL) (1.0 g/body/day for 2–3 days), and platelet transfusions [2, 9–12]. If the bleeding tendency appears to be critical, platelet transfusions in conjunction with IVIG and mPSL need to be considered.
Previous studies reported the efficacy of intravenous mPSL as the first-line treatment [15–17]. von dem Borne et al. investigated the effects of high-dose intravenous mPSL in the treatment of patients with their first attack of ITP and compared them with those of IVIG and oral prednisolone [15]. Their findings demonstrated that high-dose mPSL (HD mPSL) was as effective as IVIG. However, the effects of HD mPSL were transient in all our patients, similar to IVIG, and maintenance treatment using a low oral dose of prednisolone was necessary.
In 2002, Godeau et al. performed a randomized multicenter trial that compared IVIG and HD mPSL with or without oral prednisone. Their findings indicated that IVIG and oral prednisone were more effective than HD mPSL and oral prednisone in adults with severe ITP; however, the latter treatment was effective and tolerated well.
According to these findings, intravenous mPSL is as effective as IVIG in terms of response frequency with no reported side effects. The response to intravenous mPSL was found to be faster than that to oral corticosteroids, whereas the response to mPSL was transient and low-dose oral corticosteroids were required to maintain the platelet count [15].
4 Dexamethasone
Although prednisolone or mPSL is effective for ITP patients, improvements are often transitory. Patients who require long-term oral prednisolone therapy develop various side effects. Since pulsed high-dose dexamethasone (HD-DEX) is tolerated well and effective in patients with plasma cell neoplasms, Anderson reported efficacy with a similar HD-DEX regimen (six cycles of HD-DEX: 40 mg/day for 4 days every 28 days) in ten refractory ITP patients [18]. All patients had increased platelet counts, and long-term effects were observed for at least 6 months after the last cycle of treatments. No serious side effects were detected. Although the response rate in the study by Anderson was 100%, a similar protocol using HD-DEX was not as effective for ITP patients in other small cohort studies [19–26]. Therefore, based on the findings of these small cohort studies, the efficacy of HD-DEX remains controversial.
In 2003, Cheng et al. reported the effectiveness of HD-DEX as an initial treatment for 125 ITP patients [27]. The initial regimen was a single course of oral DEX (40 mg/body/day for 4 consecutive days). The findings obtained were impressive because the initial response rate was 85%, the relapse rate was 50%, and the sustained response rate was 42%. Moreover, a second therapy course using HD-DEX was effective in all relapsed patients. In 2007, Mazzucconi et al. reported the findings of two different prospective pilot studies: a monocenter study and multicenter study, using HD-DEX in newly diagnosed, untreated ITP patients [28]. In their multicenter study, 95 patients with severe ITP were treated using HD-DEX (oral or intravenous DEX 40 mg/body/day for 4 consecutive days, every 14 days, for 4 cycles). The response rate was 85.6% and relapse-free survival at 15 months was 81%. These findings [27, 28] suggested that it is possible to shorten the duration and reduce the adverse effects of corticosteroid treatment by using HD-DEX. Wei et al. very recently performed a prospective multicenter randomized trial to compare the efficacy and safety of HD-DEX and conventional prednisone for newly diagnosed ITP patients [29]. In this study, 192 patients were randomized to HD-DEX (oral 40 mg/body/day for 4 days, one or two courses) or prednisone (1.0 mg/kg/day for 4 weeks and then tapered). One or two courses of HD-DEX resulted in better outcomes both in overall initial response rates (82.1% vs 67.4%) and complete response rates (50.5% vs 26.8%) than those with prednisone. Moreover, the time to a response with HD-DEX was shorter than that with prednisone.
According to the findings of these recent large cohort studies [27–29], one to four courses of HD-DEX worked more effectively and rapidly than other corticosteroid treatments. A large number of reviews and guidelines have described, but not recommended HD-DEX because supporting evidence has been limited.