Intention to treat: The management of connective tissue disease-related immune thrombocytopenia

Immune thrombocytopenia (ITP) is a familiar complication of connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) and Sjögren syndrome (SS).1-3 The pathophysiology of CTD-ITP resembles that of primary ITP, namely, decreased platelet production and increased platelet destruction resulting mainly from autoantibody-mediated processes.4 However, it remains to be determined how and why checkpoint-specific impairments during the development of megakaryocytes and their progenitors, hematopoietic niche disturbance, and excessive platelet clearance occur in CTD-ITP.5 Over the past decade, several novel treatments have emerged and improved the prognosis of primary ITP and CTD-ITP. However, scheduling individualized treatments presents a new challenge. From a practical point of view, the concept of “intention to treat” can be the compass for managing CTD-ITP (Figure 1). The priority is to determine whether patients need intervention and what will be the treatment goal, the accumulative insight from which could potentially point us to the “true north”—a general criterion maximizing the effect of several lines of treatments currently available. Therapeutic guidelines for primary ITP and CTD-ITP suggest that treatment should be initiated in adult patients with platelet counts <30 × 109/L. Intervention may be indicated for patients with both elevated platelet counts and risk of bleeding.6, 7 In contrast, platelet counts >50 × 109/L represent a safe threshold or a partial remission/response and a platelet count >100 × 109/L indicates complete remission.7 In this manner, we may adapt the intention to treat and the therapeutic intensity according to the measured platelet counts. The second arm of the compass relies on multiple factors and the specific pathophysiologies of CTD-ITP that are intertwined with treatment responses. A previous study on SLE-ITP proposed that patients with bone marrow megakaryocyte counts <20/slide had significantly poor responses to immunosuppressant therapy.8 A study on SS-ITP reported a bone marrow megakaryocyte count of <6.5/slide as the immunosuppressant resistance cut-off.2 Despite the observed variations among studies in terms of their reported bone marrow megakaryocyte counts, this parameter nonetheless reflects platelet production capacity and predicts the treatment response in CTD-ITP. Patients aged >50 years had relatively higher rates of failure to respond to immunotherapy than those in other age groups. Hence, patient age must also be considered in the intention-to-treat process.9 The presence of high-risk antiphospholipid antibodies (aPL) in CTD-ITP (including multiple positivities for—or high titers of—anti-cardiolipin, anti-β2-glycoprotein-I, lupus anticoagulant, and anti-complex phosphatidylserine-prothrombin) may be associated with intravascular microthrombosis-induced platelet consumption and require specific treatments. Glucocorticoids (GCs) (with or without intravenous immunoglobulin [IVIg]) comprise first-line CTD-ITP treatments and have strong pharmacological effects on various aspects of ITP pathogenesis.3, 7 Hence, GCs may (a) decrease antibody-mediated platelet clearance by suppressing autoimmunity and (b) increase platelet production by stimulating megakaryocyte maturation in the bone marrow.4 IVIg blocks autoantibody-induced platelet clearance by saturating the Fcγ receptor.4, 10 Although this effect is rapid, it is also usually unsustainable.3, 7 While ~60%–80% of all patients respond to this first-line treatment, far fewer of them could sustain remission.3, 6 For this reason, second-line treatments with either immunosuppressants or non-immunotherapeutic agents are often necessary to maintain a prolonged therapeutic response and avoid the toxicity associated with long-term GC exposure.11, 12 B-cell-targeted therapy is now a mainstream CTD-ITP treatment. The chimeric monoclonal CD20 antibody rituximab (RTX) depletes autoreactive B.7 In primary ITP, 60% and 40% of all patients being given RTX in combination with GCs presented overall and complete responses, respectively,13 and these responses were sustained for >2 years in ~50% of all patients.14 RTX data were also robust for all CTD-ITP cases in general and for refractory cases in particular.15 In CTD-ITP, low RTX doses in the range of 400–1000 mg divided into two to four infusions were effective and well-tolerated, and the overall response rate was ~80%.3, 16 Propensity score-matched case–control data demonstrated that the therapeutic efficacy of RTX was superior to that of cyclosporine and other immunosuppressants.9 Azathioprine, cyclosporine, and mycophenolate mofetil are nonetheless viable treatment options when GC administration must be spared and for CTD-ITP patients who have inadequately responded to first-line therapies.7, 12 Thrombopoietin receptor agonist (TPO-RA) elicited good (>60%) and rapid (within weeks) treatment responses in ITP. TPO-RA therapy could sustain a response for ≤8 years. Moreover, the response persisted in one-third of all primary ITP cases even after the TPO-RA intervention was discontinued.17 TPO-RA acts on megakaryocyte receptors and promotes the development and differentiation of these cells. It also induces platelet release.4 Eltrombopag is an orally administered, US Food and Drug Administration-approved TPO-RA that treats both primary ITP and CTD-ITP. A favorable response to the drug was achieved in 70%–80% of all patients within 3–4 weeks.18, 19 However, the response was attenuated over time, and eltrombopag induced thrombosis in certain patients with aPL. Notwithstanding, TPO-RA may be an excellent bridging therapy in combination with immunotherapy for the treatment of refractory CTD-ITP. Though ITP with positive aPL is not rare, patients with this condition may nonetheless fail to meet the criteria of an anti-phospholipid syndrome (APS) diagnosis as they present no overt thromboembolic or obstetric events. The intention to treat with anticoagulant should be adapted to the presence of APS or a high aPL risk profile. Anticoagulants are indicated in cases where the platelet counts are >50 × 109/L.5 Another treatment target is mammalian target of rapamycin (mTOR), a key molecule associated with T-cell activation in SLE-ITP pathogenesis.20 In refractory CTD-ITP and primary ITP, the ranges of the overall and complete response rates to the mTOR inhibitor sirolimus were 66.7%–85% and 40%–64.3%, respectively, and there were no severe adverse effects.21-23 The mTOR pathway is associated with endothelial cell dysfunction and, by extension, thrombogenesis and platelet consumption in APS.24 A pilot study showed that sirolimus monotherapy substantially increased platelet counts in primary APS-related thrombocytopenia.25 Hence, sirolimus is an ideal candidate therapy for patients with CTD-ITP who are at high risk of aPL. Other novel CTD-ITP treatments are experimental optional third-line therapies for refractory ITP cases. New B-cell-targeted treatments such as anti-BAFF/APRIL, anti-CD38, and Bruton's tyrosine kinase inhibitor have been used to effectively manage difficult SLE-ITP cases according to anecdotal reports.3 Here, we introduce two promising non-immunomodulators with different modes of action that could potentially treat primary ITP and, eventually, CTD-ITP. Desialylation of the glycoproteins on platelet surfaces increased thrombocyte clearance by hepatic Kupffer cells via the Ashwell–Morrell receptors.26 Oseltamivir is a widely used anti-influenza agent and a desialylation inhibitor. A multicenter randomized trial repurposed oseltamivir as therapy for newly diagnosed primary ITP and demonstrated that by day 14, the patients in the dexamethasone plus oseltamivir group had significantly higher initial response rates (86%) than those in the dexamethasone group (66%). Moreover, the patients in the former group presented a higher 6-month sustained response rate (53%) than those in the latter group (30%).27 All-trans retinoic acid (ATRA) is implicated in several cell proliferation and differentiation processes. It rescued impaired megakaryopoiesis in ITP bone marrow and equilibrated macrophage polarization by regulating the complement-interleukin-1β loop.28 In a clinical trial, the sustained response rate was higher and stronger in primary ITP patients given ATRA plus high-dose dexamethasone than it was in those treated with dexamethasone alone.29 Furthermore, the combination of ATRA and low-dose RTX elicited 80% overall and 61% sustained response in refractory and relapsed primary ITP.30 Interdependent pathological mechanisms ranging from platelet production to destruction challenge therapeutic efficacy in CTD-ITP. However, appropriate response-directed treatment combinations could overcome this obstacle. GCs alone or in combination with intravenous immunoglobulin now constitute standard CTD-ITP therapy. Nevertheless, recent research has also displayed the efficacy of the monoclonal antibody RTX and TPO-RA in the control of this condition. The application of individualized medicine for the management of CTD-ITP is becoming a reality as the intention-to-treat approach is being implemented and the number of novel treatment options increases. YaKai Fu and Liling Zhao drafted the manuscript. Shuang Ye edited and finalized the manuscript. None. Authors declared no conflict of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.