Evaluation of the efficiency of hydroxychloroquine in treating children with immune thrombocytopenia (ITP)
Authors: Ombeline Roche, Nathalie Aladjidi, Josué Rakotonjanahary, Guy Leverger, Thierry Leblanc, Caroline Thomas, Marlène Pasquet, Mary‐France Courcoux, Sophie Bayart, Marion Gilibert‐Yvert, Bénédicte Neven, Pierre Quartier, Isabelle Pellier
Journal: American Journal of Hematology (2017)

Immune thrombocytopenia (ITP) is a benign hematologic disease caused by an acquired immune disorder. Therapeutically, the decision to treat and the type of treatment are controversial due to the spontaneous recovery in certain cases and the low incidence of severe hemorrhagic accidents.1 In the case of children, the Buchanan score can accurately predict the risk of bleeding and propose a course of action.2 The two main first-line treatments are immunoglobulins and corticosteroids, without favoring one over the other.3, 4 Second-line treatments are diverse and numerous. Their prescription is not hierarchical and their administration depends on the severity of the bleeding and each clinician's habits. Hydroxychloroquine (Plaquenil®) is an antimalarial drug with inflammatory properties. Godeau's team5 conducted a retrospective study between 1990 and 2008 on 40 patients with ITP and positive for antinuclear factors (ANF). The results showed the treatment's efficiency (60% response rate) and a prolonged immune response. There were no adverse effects. No such study has been published in a pediatric population. The aim of the study was to evaluate the efficiency and safety of hydroxychloroquine in the treatment of immune thrombocytopenia in children. The study included French child population, followed for either an acute, persistent or chronic ITP, diagnosed between 1998 and 2012 and treated with hydroxychloroquine (Plaquenil®) between 2002 and 2013. The children were recruited from the database OBS'CEREVANCE of CEREVANCE, the French National Reference Centre for the study and monitoring of pediatric autoimmune cytopenias (Bordeaux, France). Children aged 0-18 years who met the criteria of ITP and were treated with hydroxychloroquine as a second-line treatment were included in the study. For each patient, we identified: personal and family medical history, weight, height, disease stage and Buchanan score to assess the severity of the clinical impact at diagnosis, at the introduction of hydroxychloroquine and at later stages of the treatment. Biologically, we assessed the platelet count at diagnosis, at the introduction of hydroxychloroquine, at 6 and 12 months and at the last follow-up consultation. We also took into account the immunoglobulin levels (IgG, IgA, IgM) at diagnosis and the biological factors of autoimmunity including ANF, antiphospholipid antibodies, antithyroglobulin antibodies. Therapeutically, we identified the date of introduction of hydroxychloroquine, the administered doses, the date of a possible discontinuation of treatment and causes of treatment interruption. The different responses to the treatment were assessed according to international criteria.6 We also noted the presence of adverse effects associated with hydroxychloroquine. The analysis focused on 46 children, including 30 girls and 16 boys. The median age at diagnosis was 11.5 years [1-16.4]. Patients came from 9 centers in France. Upon the introduction of hydroxychloroquine, 6 children (13%) were in the acute phase of the disease, 13 (28.3%) in the persistent phase and 27 (58.7%) in chronic phase. The median hydroxychloroquine introduction was 14.5 months [1-156] after diagnosis. The median initial dose of treatment was 6.2 mg/kg/day [3.1-9.2]. The median Buchanan score at the time of introduction of hydroxychloroquine was 1 [0-1]. The median platelet level was 7 G/L[4-11] at diagnosis, 7 G/L [4-11] at the time of introduction of hydroxychloroquine, 59 G/L[23-134] at six months and 92 G/L [29-165] at twelve months from the beginning of treatment (Figure 1). 95.7% were screened for ANF and 54.5% were positive. The median rate of ANF in these children was 1/325. 71.7% were tested for antiphospholipid antibodies (APL) and 18.2% were positive. 60.9% were tested for thyroglobulin antibodies (ATG) and 10.7% were positive. 50% were positive for at least one of the 3 antibodies (ANF, APL, or ATG). Response to hydroxychloroquine and platelets counts Hydroxychloroquine was introduced as a second-line treatment for 80.4% of children. The median duration of the administration was 12.6 months [0.9-76] for the entire population and 23.5 months for responsive children (R or CR). 34.8% children had a complete response (CR), of which 75% were positive for at least one of the three positive antibodies. 21.7% children showed a response (R) of which 60% tested positive for at least one of the three antibodies. In children who were responsive to the treatment (either R or CR), the 6-month response rate was 30.4%, at 12 months the rate was at 56.5% and at 24 months it was around 60.8%. Out of the 16 children who had a complete response (CR), 4 relapsed after the discontinuation of hydroxychloroquine, with a median time of 1 month. Two of these had another CR again following the reintroduction of the treatment. The other two children underwent 2 or 3 other treatments, but did not have a CR. Out of the 10 children who had a response (R), one relapsed during treatment and another relapsed after discontinuation of treatment. Eighteen (39.1%) were unresponsive (NR) among which 8 (44.4%) were positive for at least one of the three positive antibodies. Nine children (19.6%) reported adverse effects, which led to the discontinuation of treatment for four of them. Thirty-six children were subject to ophthalmologic monitoring during the hydroxychloroquine treatment. Four suffered from ophthalmologic disorders due to retinal toxicity associated with the drug. The results suggest that hydroxychloroquine may be an attractive therapeutic in the treatment of children with ITP particularly acute phase and directly in second line after failure of corticosteroids and/or immunoglobulins. Furthermore, hydroxychloroquine proves to be particularly advantageous in children with autoimmune markers (FAN, ATG, APL) positive without lupus. This implies that clinicians routinely perform a complete autoimmune balance sheet to better target potentially good responders children. The serum dosage of treatment is also an important parameter to consider in monitoring these children, as shown by the practices of our colleagues in adult patients. Nevertheless, the small size of this study does not allow us to conclude with a satisfactory statistical power on the effectiveness of treatment. These results need to be confirmed by a prospective multicenter, randomized, and controlled so that the practices regarding the use of hydroxychloroquine can be harmonized within national guidelines.