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A. Tiede et al.
Figure 3. Recommendations regarding Immunosuppressive therapy in patients with acquired hemophilia A. Comparison of immunosuppressive therapy regimens recommended in the 2009 international recommendations by Huth-Kühne et al.1 the GTH study10 and the current paper. FVIII; factor VIII activity; BU: Bethseda unit; CTX, cyclophosphamide.
reduced to doses used before AHA developed without relapse.2 The GTH study also included a definition for partial remission: FVIII restored to >50% and no bleeding after stopping any hemostatic treatment for at least 24 h.10
General strategy and prognostic factors
The 2009 international AHA guidelines recommended starting IST in all patients with AHA immediately follow- ing diagnosis.1 This recommendation was mainly based on the high bleed-related mortality in earlier studies and the observation that the initial bleeding tendency was not predictive of later major or even fatal bleeding.61 Initial treatment with corticosteroids alone or in combination with cyclophosphamide was recommended for up to 6 weeks, while second-line therapy with rituximab was suggested if first-line IST failed or was contraindicated (Figure 3).
The GTH-AH 01/2010 study protocol was designed as a variant of this recommendation and was the first IST protocol investigated prospectively.10 Patients were enrolled ≤7 days after starting any IST, and follow-up data were collected weekly until complete remission was achieved. The 1-year survival rate was 68%. The most frequent cause of death among the 34 patients who died was infection (n=16), followed by cardiovascular disor- ders (n=6), underlying disorders (n=3), and bleeding (n=3). Fourteen deaths were considered to be directly related to IST. These results established that IST-related mortality, in particular infection, exceeds the current risk of fatal bleeding in AHA. Patients with a poor World Health Organization (WHO) performance status (>2) at presentation had a 4-fold increased risk of mortality. Therefore, careful individual consideration of the require- ment for and contraindications against IST, its intensity and timing is warranted in frail patients with AHA and should be a priority for future research. IST should be stopped if severe side effects to treatment develop.
We recommend IST in all patients with AHA. However, partic- ular caution should be exercised in frail patients (GRADE 1B).
The success of IST, in particular the time to achieve remission, varies largely among patients. In the GTH study, 85/102 (83%) patients achieved a partial remission after a median time of 5 weeks (range, 1−52 weeks).10 FVIII:C at presentation was the most important prognos- tic factor; patients with FVIII <1% achieved partial remis- sion less often compared with other patients (77 vs. 89%, respectively) and after a significantly longer time on IST (43 vs. 24 days, respectively). Anti-FVIII IgA autoantibod- ies were predictors of relapse as observed in 45% of patients with anti-FVIII IgA titers >1:80. These data sug- gest that IST should be individualized in patients with AHA according to baseline characteristics, although inter- ventional studies with stratified protocols have not been performed.
We suggest using prognostic markers (FVIII activity, inhibitor titer, if available) to individualize IST (GRADE 2B).
The benefit of combining corticosteroids with other immunosuppressants for first-line therapy is uncertain and cannot be concluded from the published observation- al studies. Combination therapy shortened the time to remission in the EACH2 registry7 but not in the UK sur- veillance study.2 GTH data indicated that achieving par- tial remission within 21 days of steroid therapy was unlikely (negative predictive value, 84%) if patients had FVIII <1% or an inhibitor titer >20 BU.10 We, therefore, suggest combination therapy in these patients. In all other patients (i.e., those with FVIII ≥1% and inhibitor ≤20 BU), we suggest using steroids alone, because the benefit of more intense regimens is uncertain, and the risk of infec- tious complications currently exceeds the risk of bleeding.
We suggest that patients with FVIII ≥1 IU/dL and inhibitor titer ≤20 BU at baseline receive first-line treatment with cortico- steroids alone for 3−4 weeks (GRADE 2B).
We suggest combining corticosteroids with rituximab or a cyto-
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