Journal of Clinical Medicine Review Emerging Therapies in Immune Thrombocytopenia Sylvain Audia 1,2,* and Bernard Bonnotte 1,2 1 Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Cytopénies Auto-Immunes de l’adulte, Centre Hospitalo-Universitaire Dijon Bourgogne, 21000 Dijon, France; [email protected] 2 Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, INSERM, EFS BFC, UMR1098, Université de Bourgogne Franche-Comté, 21000 Dijon, France * Correspondence: [email protected]; Tel.: +33-380-293-432 Abstract: Immune thrombocytopenia (ITP) is a rare autoimmune disorder caused by peripheral platelet destruction and inappropriate bone marrow production. The management of ITP is based on the utilization of steroids, intravenous immunoglobulins, rituximab, thrombopoietin receptor agonists (TPO-RAs), immunosuppressants and splenectomy. Recent advances in the understanding of its pathogenesis have opened new fields of therapeutic interventions. The phagocytosis of platelets by splenic macrophages could be inhibited by spleen tyrosine kinase (Syk) or Bruton tyrosine kinase (BTK) inhibitors. The clearance of antiplatelet antibodies could be accelerated by blocking the neonatal Fc receptor (FcRn), while new strategies targeting B cells and/or plasma cells could improve the reduction of pathogenic autoantibodies. The inhibition of the classical complement pathway that participates in platelet destruction also represents a new target. Platelet desialylation has emerged as a new mechanism of platelet destruction in ITP, and the inhibition of neuraminidase could dampen this phenomenon. T cells that support the autoimmune B cell response also represent an interesting target. Beyond the inhibition of the autoimmune response, new TPO-RAs that stimulate platelet production have been developed. The upcoming challenges will be the determination of predictive factors of response to treatments at a patient scale to optimize their management. Citation: Audia, S.; Bonnotte, B. Emerging Therapies in Immune Keywords: immune thrombocytopenia; Syk inhibitor; BTK inhibitor; FcRn; desialylation; TPO-RA Thrombocytopenia. J. Clin. Med. 2021, 10, 1004. https://doi.org/10.3390/ jcm10051004 Academic Editor: Marie Scully 1. Introduction Immune thrombocytopenia (ITP) is a rare autoimmune disorder with an incidence Received: 26 January 2021 of 2.9/100,000 person-years [1,2]. The major complication is bleedings, occurring in 60% Accepted: 18 February 2021 of the patients, with serious bleeding in 6%, and intracranial hemorrhage in only 0.4% [1]. Published: 2 March 2021 These bleedings are favored by a platelet count <20 G/L, the use of anticoagulants or non-steroidal anti-inflammatory drugs [1]. Publisher’s Note: MDPI stays neutral Until now, the management of primary ITP has relied on the utilization of a lim- with regard to jurisdictional claims in ited number of drugs, mostly steroids, intravenous immunoglobulins (IVIg), rituximab, published maps and institutional affil- thrombopoietin receptor agonists (TPO-RAs) and immunosuppressants, or splenectomy [3]. iations. Treatments are indicated in the case of bleedings, best assessed by a clinical score [4], usu- ally when the platelet count is <20–30 G/L or <50 G/L for patients with other risk factors of bleedings [3]. The nature of ITP is also considered for the choice of treatments. Considered as Copyright: © 2021 by the authors. primary in 80% cases, ITP is secondary or associated to another disease (lymphoma, Licensee MDPI, Basel, Switzerland. systemic autoimmune diseases, infections or primary immune deficiencies) in around This article is an open access article 20% [2]. For example, hydroxychloroquine could be of interest in the case of lupus or distributed under the terms and presence of antinuclear antibodies [5] and rituximab will be favored in case of ITP associated conditions of the Creative Commons with lymphoid hemopathy not requiring chemotherapy. Attribution (CC BY) license (https:// The course of ITP is also considered in treatment algorithm. ITP is defined as newly creativecommons.org/licenses/by/ diagnosed (<3 months after diagnosis), persistent (3–12 months after diagnosis) and chronic 4.0/). J. Clin. Med. 2021, 10, 1004. https://doi.org/10.3390/jcm10051004 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 19 J. Clin. Med. 2021, 10, 1004 2 of 19 chronic (>12 months after diagnosis). Around 70% of adult patients enter the persistent (>12 months after diagnosis). Around 70% of adult patients enter the persistent phase phase and 60% the chronic phase. As remission could spontaneously happen or be ob- and 60% the chronic phase. As remission could spontaneously happen or be obtained tained with short-course treatments in the first year, irreversible therapy such as splenec- with short-course treatments in the first year, irreversible therapy such as splenectomy is tomy is excluded before 12 months of evolution. Short-term or sequential therapies are excluded before 12 months of evolution. Short-term or sequential therapies are favored in favored in the early phase, as 30% of patients will enter remission within the first 3 months the early phase, as 30% of patients will enter remission within the first 3 months following following diagnosis [1,3]. diagnosis [1,3]. ITP patients patients are are also also at at increased increased risk risk of infe of infectionsctions [1], [that1], thatare partly are partly favored favored by treat- by treatments,ments, highlighting highlighting the need the for need a broader for a broader choice choiceof treatments of treatments with fewer with risks fewer of infec- risks oftious infectious complications. complications. New ther Newapeutic therapeutic approaches approaches have been have proposed been proposed in the last in few the lastyears few and years are currently and are currentlyavailable or available under investigation. or under investigation. The purpose The of this purpose review of is this to reviewsummarize is to these summarize new treatments these new and treatments to situat ande their to situate mechanisms their mechanisms of action in ofITP action patho- in ITPgenesis. pathogenesis. 2. ITP Pathogenesis ITP is due to an autoimmuneautoimmune peripheral destructiondestruction ofof plateletsplatelets byby theirtheir recognitionrecognition by autoantibodies (Figure(Figure1 1),), targeting targeting different different glycoproteins glycoproteins (GPs), (GPs), mostly mostly GPIIb/IIIa GPIIb/IIIa and GPIb/IX, that that mediate mediate antibody-dependent antibody-dependent cellular cellular phagocytosis (ADCP), antibody- dependent cellularcellular cytotoxicity cytotoxicity (ADCC) (ADCC) and and complement complement dependent dependent cytotoxicity cytotoxicity (CDC) (CDC)[6,7]. Opsonized[6,7]. Opsonized platelets platelets are phagocytosed are phagocyt byosed splenic by splenic macrophages macrophages in an Fc inγ receptoran Fcγ receptor (FcγR)- dependent(FcγR)-dependent mechanism mechanism [8]; splenic [8]; splenic macrophages macrophages also playalso play the rolethe role of major of major antigen- anti- presentinggen-presenting cells cells in ITP in [ 9ITP]. The [9]. desialylationThe desialylation of platelets of platelets is another is another mechanism mechanism that could that becould involved be involved in platelet in platelet destruction, destruction, desialylated desialylated platelets platelets being recognized being recognized by the Ashwell– by the MorellAshwell–Morell receptor expressedreceptor expressed by hepatocytes by hepato andcytes being and destroyed being destroyed in the liverin the in liver a Fc inγR- a independentFcγR-independent mechanism mechanism [10]. Antiplatelet [10]. Antiplatelet antibodies antibodies are produced are produced by autoreactive by autoreactive B cells stimulatedB cells stimulated by T follicular by T follicular helper cellshelper that cells provide that provide activation activation signals throughsignals through CD40 ligation CD40 andligation interleukin and interleukin (IL)-21 [11 (IL)-21]. Overall, [11]. thisOverall, autoimmune this autoimmune response isresponse favored is by favored a deficiency by a ofdeficiency regulatory of regulatory T cells (Treg) T cells [12, 13(Treg)]. There [12,13]. is also There insufficient is also insufficient bone marrow bone production marrow pro- of plateletsduction of resulting platelets from resulting both anfrom immune both an response immune directed response against directed megakaryocytes against megakar- [14] butyocytes also [14] from but inappropriate also from inappropriate concentration conc of thrombopoietinentration of thrombopoietin (TPO) [15], the (TPO) major [15], growth the factormajor ofgrowth megakaryocytes. factor of megakaryocytes. FigureFigure 1.1. PathogenesisPathogenesis ofof immuneimmune thrombocytopeniathrombocytopenia andand sitessites ofof drugdrug action.action. ImmuneImmune thrombocytopeniathrombocytopenia resultsresults fromfrom bothboth aa peripheralperipheral destructiondestruction of platelets,platelets, mostly occurring in the spleen, and an insufficientinsufficient bone marrow production. Peripheral platelet destruction is supported by antiplatelet antibodies produced by plasma cells that differentiate from B Peripheral platelet destruction is supported by antiplatelet antibodies produced by plasma cells that differentiate from B cells stimulated by T follicular helper cells through the CD40/CD154 axis and IL-21 production.