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Diagnosis and treatment of acquired hemophilia A
toxic agent for first-line therapy in patients with FVIII <1 IU/dL or inhibitor titer >20 BU (GRADE 2B).
In the GTH study, 23 patients had a continuous improvement of their FVIII:C and/or inhibitor titer while not achieving partial remission during the first 3 weeks on steroids.10 These patients were not escalated to sec- ond-line IST and all achieved partial remission after a median of 29 days.
We suggest extending observation in patients who do not achieve remission with first-line IST but have continued improvement of FVIII activity and inhibitor titer (GRADE 2B).
Patients not responding to steroids after 3 weeks were escalated to second-line therapy with cyclophosphamide, and later rituximab, in the GTH study. Eighty-three per- cent of these patients achieved remission.
We suggest second-line therapy with rituximab or a cytotoxic agent, whichever was not used during first-line therapy (GRADE 1B).
Corticosteroids
Corticosteroid therapy with prednisolone or pred- nisone 1 mg/kg/day PO for 4−6 weeks was suggested in the 2009 international AHA recommendations.1 This reg- imen was also used in the GTH study.10
For corticosteroid therapy, we suggest prednisolone or pred- nisone at a dose of 1 mg/kg/day PO for a maximum of 4−6 weeks (followed by tapered withdrawal) (GRADE 2B).
Rituximab
Second-line therapy with rituximab for inhibitor eradi- cation was recommended in the 2009 international AHA recommendations.1 Rituximab is often used at the licensed dose for the treatment of non-Hodgkin lymphoma (i.e., 375 mg/m2/week), but has also been used in lower doses of 100 mg/week in some reported cases.62-65 The drug is licensed for the treatment of rheumatoid arthritis at a fixed dose of 1,000 mg on days 1 and 15.66 This regimen has also been used in immune thrombocytopenia.67,68 Although not licensed for the treatment of AHA, we sug- gest adding rituximab to first-line IST in patients with poor prognostic markers, in those with contraindications against corticosteroids, or as second-line therapy.
We suggest rituximab at a dose of 375 mg/m2 weekly for a maximum of four cycles (GRADE 2B).
Cytotoxic agents
Cyclophosphamide therapy was recommended at a dose of 1.5−2 mg/kg/day PO in the 2009 international AHA recommendations.1 Intravenous pulse therapy of cyclophosphamide 500−1,000 mg/m2 is licensed for the treatment of severe lupus nephritis and Wegener granulo- matosis, although there is no experience in AHA.69 Recently, the use of mycophenolate mofetil (MMF) was reported in a retrospective collection of 11 AHA patients.70 MMF was started at 1 g/day and increased to 2 g/day after 1 week. Among seven patients given MMF together with prednisolone as first-line IST, one complete and five partial remissions were achieved after 4 to 77 weeks; among four patients receiving MMF for second- line IST after a median of 14 weeks of other treatments, three complete remissions and one parital remission were observed. Close monitoring for leukopenia, thrombocy- topenia, and infections is required during treatment with any cytotoxic agent. These agents should not be used in pregnancy or in women who are breastfeeding.
As cytotoxic therapy, we suggest cyclophosphamide at a dose of 1.5−2 mg/kg/day PO for a maximum of 6 weeks, or MMF at a dose of 1 g/day for 1 week, followed by 2 g/day (GRADE 2B).
Immunoadsorption, immune tolerance regimens and immunoglobulins
Immunoadsorption protocols have been used success- fully to deplete inhibitors in patients with AHA. The modified Bonn-Malmö protocol combined immunoad- sorption with high-dose FVIII, intravenous immunoglob- ulins and immunosuppression.71 Inhibitors were eliminat- ed after a median of 3 days. Whether the overall response rate is superior to that achieved with IST alone remains unclear, as does the relative contribution of FVIII and immunoglobulins in this regimen. We, therefore, suggest that this protocol is used only in patients with particularly severe bleeding or those who are resistant to other thera- py.
Similarly to immune tolerance in hemophilia A with inhibitors, high-dose FVIII has been combined with IST by several investigators in AHA.71-74 However, a conclu- sion as to whether FVIII increased the efficacy of IST can- not be reached based on these studies due to the lack of a control group for comparison. We, therefore, suggest this treatment only in patients with life-threatening bleeding in whom the available hemostatic therapies have failed.
We do not recommend the use of high-dose human FVIII for immune tolerance induction in AHA (GRADE 2C).
High-dose intravenous immunoglobulins are known to be effective in idiopathic thrombocytopenic purpura; however, they had little or no effect in patients with AHA in the one currently available study on this therapeutic strategy.75
We do not recommend use of high-dose intravenous immunoglobulins for inhibitor eradication in patients with AHA (GRADE 1B).
Follow-up
Adverse events occurred in 66% of patients in the GTH registry (including IST-related events in 50%): 25% of the events occurred after more than 100 days.10 Relapse occurred in 12−18% of EACH2 patients after a median time of 138 days.7 Given the risks of adverse events and of recurrence, patients should be closely monitored until they achieve complete remission and for several months thereafter. Monitoring of FVIII:C is more sensitive than APTT for detecting recurrence.
We recommend follow-up after complete remission, using FVIII:C monitoring monthly during the first 6 months, every 2−3 months up to 12 months, and every 6 months during the second year and beyond, if possible (GRADE 1B).
Pregnancy-associated acquired hemophilia A
Hemostatic therapy and the response to it were similar in 42 women with pregnancy-associated AHA as com- pared with other patients in the EACH2 registry.5 A total of 70% of the women received steroids alone for IST, while the rest received steroids and rituximab, cytotoxic agents, or intravenous immunoglobulins. The success rates and times to remission were similar in these women compared with those in other AHA patients in the reg- istry. The mortality rate was lower than in the other patients, possibly because of the younger age of women with pregnancy-associated AHA, and the risk of relapse
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