Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists

Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with... Abstract Objectives The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. Methods This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Results We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Conclusion Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy. immune thrombocytopenia, systemic lupus erythematosus, antiphospholipid syndrome, thrombopoietin-receptor agonists, thrombosis events, adverse events Rheumatology key messages Thrombopoietin-receptor agonists are very effective in SLE immune thrombocytopenia. Serious unexpected venous and arterial thrombosis were observed in patients with APS or aPLs. aPLs should be systematically screened before initiation of thrombopoietin-receptor agonists in patients with SLE. Introduction SLE is frequently associated with immune thrombocytopenia (SLE-ITP), representing 7–30% of cases [1]. The pathophysiology is probably multifactorial, including antiplatelet glycoprotein antibodies, as in ITP, but also immune complexes, and antibodies against thrombopoietin and thrombopoietin receptor [1]. SLE-ITP is defined as platelet count <100 × 109/l without any other identifiable cause [2] and is usually mild to moderate and does not need any specific treatment. SLE can be associated with APS that is frequently responsible for moderate asymptomatic thrombocytopenia (>100 × 109/l). Severe thrombocytopenia in APS (APS-ITP, <50 × 109/l) is rarer and is mainly attributable to the presence of anti-platelet antibodies, suggesting a pathophysiology very similar to that of primary ITP [3]. When treatment is required, management is similar to that for ITP because an immune-mediated mechanism is inferred in the pathogenesis of SLE-ITP and APS-ITP. Thus, first-line treatment relies on CSs and IVIGs for severe or life-threatening thrombocytopenia [1, 4]. A response to a short course of CSs or IVIGs provides some evidence favouring an immune mechanism. HCQ has been shown to improve the rate of sustained response [5]. Immunosuppressive agents, such as AZA, ciclosporin or CYC [6, 7], or splenectomy [8] have been used for a long time as second-line treatments, but rituximab has emerged as an effective and relatively safe option for second-line treatment of SLE-associated immune cytopenias [9]. However, a significant number of patients will not respond to these treatments or will relapse [10]. More recently, romiplostim and eltrombopag, two thrombopoietin-receptor agonists (TPO-RAs), approved as second-line therapy for primary ITP, have demonstrated clinical efficacy with sustained improvement of platelet count in ∼70–80% of cases, with reduced bleeding [11, 12]. Currently, the experience with this class of agents in SLE is not well described, and their effectiveness and tolerance in SLE need evaluation. Here, we describe the largest cohort of SLE-ITP patients exposed to TPO-RAs. Methods This was a multicentre retrospective cohort study. We included patients presenting SLE-ITP treated with TPO-RAs from 2009 to 2016. All participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Clinical data were collected retrospectively from medical charts for each patient by using a standardized questionnaire. The study was approved by an institutional review board (Comité de Protection des Personnes Ile de France-IX), with no informed consent being required according to the French law (Jardet), and was conducted in accordance with the Declaration of Helsinki. ITP was defined according to the international working group definitions [13]. In line with international recommendations for ITP, a bone marrow smear biopsy was performed in patients >60 years old and in patients not responding to CSs or IVIGs [14]. SLE was defined according to international guidelines (ACR) [15]. APS was defined according to the revised Sapporo criteria [16]. We ascertained age, gender, date at diagnosis of SLE and ITP and previous medications used for managing thrombocytopenia, including the duration of high-dose CS use and number of IVIG infusions. Bleeding severity at the time of diagnosis was evaluated by a standardized bleeding score with censored data for age [17]. We reviewed laboratory results, including complete blood counts at diagnosis and lowest platelet count and autoantibodies (ANA and presence of aPLs: aCL, anti-β2-glycoprotein 1 antibody and lupus anticoagulant). For TPO-RAs, we reviewed the type, date of commencement, duration, dose, side-effects and reason for interruption and therapeutic switch. Response (R) and complete response (CR) were defined according to standardized international criteria (CR: platelet count >30 × 109/l with at least a doubling of the baseline value or >100 × 109/l). Non-response (NR) was defined as absence of platelet count increase >30 × 109/l with at least a doubling of the baseline count or the need for rescue therapy (IVIGs and/or CSs) [13]. Literature review We searched MEDLINE via PubMed for all articles published between 2000 and 2017 by using the MeSH terms: Immune Thrombocytopenia (ITP) and Systemic Lupus Erythematosus (SLE), Romiplostim or Eltrombopag and Systemic Lupus Erythematosus. We found 247 articles and selected 13 describing 28 patients with SLE-ITP treated with TPO-RAs: 15 patients from 12 case reports [18–29], and 13 patients from a cohort of patients with secondary ITP treated with TPO-RAs [30]. Results Characteristics of ITP patients A total of 18 patients (14 females, 78%) with definite SLE according to ACR criteria were included in the study. Patient characteristics and results are summarized in supplementary Table S1, available at Rheumatology online. ITP preceded SLE diagnosis for 3 patients, was simultaneous with SLE diagnosis for 3, and occurred during the course of SLE for 12. Ten (55%) patients had aPLs, five (27%) with definite APS. The mean platelet count at ITP diagnosis was 36 × 109/l (range: 3–79×109/l), with severe bleeding manifestations in three patients. All patients received CSs and HCQ. Besides these drugs, patients received a median of 4 (interquartile range: 3–5) previous treatment lines for ITP before the start of TPO-RAs; 13 had received rituximab, and 7 underwent splenectomy. All but one patient (with an intracranial haemorrhage) had a least a platelet count <30 × 109/l before the start of TPO-RAs. The median age was 52 years (range: 21–70 years) at TPO-RA initiation. Six patients (33%) received romiplostim, five (28%) eltrombopag and seven (39%) both sequentially. Outcome Platelet response All but one patient achieved a response with TPO-RAs overall (94%), 12/13 (92%) with romiplostim (7 CR, 5 R) and 9/12 (67%) with eltrombopag (7 CR, 2 R). Eltrombopag was switched to romiplostim for seven patients because of related adverse events (n = 2, arthralgia and elevated liver enzyme levels), no response (n = 3) or relapse (n = 2). The median delay of response was 30 days for romiplostim (range: 14–35 days) and 17.5 days for eltrombopag (range: 7–30 days). After a median follow-up of 14.7 months (interquartile range: 4.7–47.5 months) with TPO-RAs, 11/18 patients (61%) had CR, 6/18 (33%) had R, and 1/18 (6%) had no response. Two patients who received eltrombopag presented relapse after an initial CR, after 7 and 20 months, respectively. One patient who received eltrombopag showed a sustained response after stopping TPO-RAs (6 months of follow-up after discontinuation). Two patients received a short course of TPO-RAs before surgery. Safety After a median follow-up of 14.7 months (interquartile range: 4.7–47.5 months) with TPO-RAs, 8/18 (44%) patients experienced one or more adverse events during treatment: two presented arthralgia and one elevated liver enzyme concentrations. Five patients (28%) showed thrombotic events (TEs) as a side-effect (Table 1) during treatment with eltrombopag (n = 4) or romiplostim (n = 1). TEs occurred at a median of 3.5 months (range: 1–7 months) after treatment. The platelet count at the time of TE was >150 × 109/l for three patients (range: 166–484 × 109/l). Table 1 Characteristics of patients with SLE-ITP who received TPO-RAs and presented TEs Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV aβ2GP1: anti-beta-2-glycoprotein 1; CR: complete response; F: female; LMVH: low-molecular-weight heparin; LA: circulating anticoagulant; M: male; NR: no response; NS: not specified; R: response; RTX: rituximab; SLE-ITP: SLE-associated immune thrombocytopenia; TE: thrombotic event; TPO-RA: thrombopoietin-receptor agonist. Table 1 Characteristics of patients with SLE-ITP who received TPO-RAs and presented TEs Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV aβ2GP1: anti-beta-2-glycoprotein 1; CR: complete response; F: female; LMVH: low-molecular-weight heparin; LA: circulating anticoagulant; M: male; NR: no response; NS: not specified; R: response; RTX: rituximab; SLE-ITP: SLE-associated immune thrombocytopenia; TE: thrombotic event; TPO-RA: thrombopoietin-receptor agonist. Four arterial TEs occurred in four patients who received eltrombopag, with previous APS in three, and with aPL positivity without definite APS in the last patient. The arterial TEs were two myocardial infarctions, one stroke and one catastrophic APS (CAPS). CAPS occurred 6 months after TPO-RA initiation in a 67-year-old woman during rivaroxaban treatment, with good adherence to treatment. The woman presented multiple cerebral strokes, skin necrosis and myocardial infarction. The outcome was favourable, with immediate eltrombopag cessation, anticoagulation therapy, high-dose CSs, plasma exchange and IVIGs. The two other patients with APS had received aspirin before the event. Two venous TEs (pulmonary embolism and, a year later, intracranial sinus thrombosis) occurred in a 24-year-old woman (without APS or aPL positivity) who received romiplostim. She had been under low-molecular-weight heparin treatment for 1 year when the second event occurred but had stopped the treatment at this time (non-compliance). In all but one patient with TEs, TPO-RAs were immediately discontinued at the time of the TE. However, because of ITP relapse, TPO-RAs were reinitiated in threee patients receiving anticoagulation or anti-platelet therapy, with a median follow-up of 7 months (range: 1–24 months). The TPO-RA was definitely stopped in the patient with CAPS. No SLE flare was observed in patients exposed to TPO-RAs. Systematic literature review The literature included reports of 15 patients with SLE-ITP [12 females; median age 44 years (14–69)]; 14 (93%) achieved overall response (R + CR) with TPO-RAs (Table 2). In all, eight patients (53%) had received eltrombopag and seven (47%) romiplostim. Two venous TEs (7%) were reported, in one patient with aPLs (deep vein thrombosis) and in one with APS despite warfarin treatment and an INR above the target, with a fatal result [25]. CAPS occurred in a young patient who received romiplostim for 11 weeks, revealing SLE and APS. The outcome was favourable with romiplostim cessation, anticoagulation treatment, CSs and rituximab [21]. A patient presented a thrombotic microangiopathy after romiplostim treatment [18]. In a group of patients with various auto-immune diseases, including SLE-ITP and APS, Gonzáles-Lópes et al. [30] reported an incidence of 10% of TEs. In their study, two out of six patients with APS developed TEs (superficial phlebitis and pulmonary embolism) [30]. A stroke occurred in one patient with SLE-ITP, with no more details in the review [30]. Table 2 Literature review of 15 case reports describing the use of TPO-RAs for SLE-ITP Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Aba: abatacept; aβ2GP1: anti-beta-2-glycoprotein 1; AVK: antivitamin K; CR: complete response; Elt: eltrombopag; F: female; M: male; NR: non-response; NS: not specified; Romipl: romiplostim; RTX: rituximab; R: response; SLE-ITP: SLE associated immune thrombocytopenia; Spl: splenectomy; Toci: tocilizumab; TPO-RA: thrombopoietin-receptor agonist. Table 2 Literature review of 15 case reports describing the use of TPO-RAs for SLE-ITP Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Aba: abatacept; aβ2GP1: anti-beta-2-glycoprotein 1; AVK: antivitamin K; CR: complete response; Elt: eltrombopag; F: female; M: male; NR: non-response; NS: not specified; Romipl: romiplostim; RTX: rituximab; R: response; SLE-ITP: SLE associated immune thrombocytopenia; Spl: splenectomy; Toci: tocilizumab; TPO-RA: thrombopoietin-receptor agonist. Discussion TPO-RAs have increased in use as second-line therapy for ITP. However, their safety has been evaluated mostly in primary ITP. We have few reports describing their use in SLE-ITP. This is the largest real-life study of patients with SLE-ITP treated with TPO-RAs. We demonstrated the drugs’ efficacy in patients with previously failure or relapse after standard therapy. The rate of response overall (90%) was very high. These results are in line with those in the literature, finding 82% response (23 of 28 cases reported [16–27] or cohort cases [30]); five patients (8%) did not achieve response. The recent Spanish cohort of secondary ITP treated with eltrombopag showed that immune- and infection-related ITP was more prone to respond to TPO-RAs than ITP secondary to neoplasia [30]. However, in addition to commonly reported adverse events, such as arthralgia and increased liver enzyme concentrations, 28% of our patients showed serious unexpected TEs, including venous and arterial thrombosis. Strikingly, four of five of these patients had APS (n = 3) or aPLs (n = 1). Four venous TEs have been reported in the literature, in patients with APS. One stroke was reported in a patient with SLE-ITP [30]. Moreover, three cases of CAPS in patients exposed to TPO-RAs, including ours, occurred in two patients with SLE associated with APS and one with primary APS [21]. It is interesting to note that we observed a CAPS on rivaroxaban, because TEs have been previously reported on direct oral anticoagulant therapy, suggesting that direct oral anticoagulant therapy should not be used in APS patients [29, 30]. These life-threatening events are per se a signal to use TPO-RAs with caution in patients with SLE and APS. The cumulative incidence of TEs was ∼5% in the two pivotal prospective trials, but they are more likely to occur in older patients; however, patients with a definite APS were excluded from these trials [19, 22]. In ITP, increased risk of TEs has been related to splenectomy, age and co-morbidity [25], but TPO-RAs may be intrinsically associated with TEs. The pathogenesis is still unclear, because both venous and arterial thrombosis occurs independently of platelet count and at any time during treatment. Indeed, a study suggested that platelets were activated with TPO-RA treatment [31]. Our study has some limitations owing to its retrospective design, including some potential selection bias and the low number of patients, but prospective trials of SLE patients exposed to TPO-RAs would be difficult to perform. To conclude, because of the prevalence of aPLs in SLE (from 20 to 40%) [32] and in light of our results, aPLs could be systematically screened before TPO-RA initiation in patients with SLE-ITP. With positivity for aPLs, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: B.G. has served as a consultant for Amgen, GSK and Novartis and received research support from Roche. M.Ma. has received research support from GSK. M.Mi. received speaker’s honoraria from AMGEN, GSK and Novartis and research support from Roche. All other authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. References 1 Velo-García A , Castro SG , Isenberg DA. 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Google Scholar CrossRef Search ADS PubMed 37 Levine JS , Branch DW , Rauch J. The antiphospholipid syndrome . N Engl J Med 2002 ; 346 : 752 – 63 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists

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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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Abstract

Abstract Objectives The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. Methods This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Results We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Conclusion Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy. immune thrombocytopenia, systemic lupus erythematosus, antiphospholipid syndrome, thrombopoietin-receptor agonists, thrombosis events, adverse events Rheumatology key messages Thrombopoietin-receptor agonists are very effective in SLE immune thrombocytopenia. Serious unexpected venous and arterial thrombosis were observed in patients with APS or aPLs. aPLs should be systematically screened before initiation of thrombopoietin-receptor agonists in patients with SLE. Introduction SLE is frequently associated with immune thrombocytopenia (SLE-ITP), representing 7–30% of cases [1]. The pathophysiology is probably multifactorial, including antiplatelet glycoprotein antibodies, as in ITP, but also immune complexes, and antibodies against thrombopoietin and thrombopoietin receptor [1]. SLE-ITP is defined as platelet count <100 × 109/l without any other identifiable cause [2] and is usually mild to moderate and does not need any specific treatment. SLE can be associated with APS that is frequently responsible for moderate asymptomatic thrombocytopenia (>100 × 109/l). Severe thrombocytopenia in APS (APS-ITP, <50 × 109/l) is rarer and is mainly attributable to the presence of anti-platelet antibodies, suggesting a pathophysiology very similar to that of primary ITP [3]. When treatment is required, management is similar to that for ITP because an immune-mediated mechanism is inferred in the pathogenesis of SLE-ITP and APS-ITP. Thus, first-line treatment relies on CSs and IVIGs for severe or life-threatening thrombocytopenia [1, 4]. A response to a short course of CSs or IVIGs provides some evidence favouring an immune mechanism. HCQ has been shown to improve the rate of sustained response [5]. Immunosuppressive agents, such as AZA, ciclosporin or CYC [6, 7], or splenectomy [8] have been used for a long time as second-line treatments, but rituximab has emerged as an effective and relatively safe option for second-line treatment of SLE-associated immune cytopenias [9]. However, a significant number of patients will not respond to these treatments or will relapse [10]. More recently, romiplostim and eltrombopag, two thrombopoietin-receptor agonists (TPO-RAs), approved as second-line therapy for primary ITP, have demonstrated clinical efficacy with sustained improvement of platelet count in ∼70–80% of cases, with reduced bleeding [11, 12]. Currently, the experience with this class of agents in SLE is not well described, and their effectiveness and tolerance in SLE need evaluation. Here, we describe the largest cohort of SLE-ITP patients exposed to TPO-RAs. Methods This was a multicentre retrospective cohort study. We included patients presenting SLE-ITP treated with TPO-RAs from 2009 to 2016. All participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Clinical data were collected retrospectively from medical charts for each patient by using a standardized questionnaire. The study was approved by an institutional review board (Comité de Protection des Personnes Ile de France-IX), with no informed consent being required according to the French law (Jardet), and was conducted in accordance with the Declaration of Helsinki. ITP was defined according to the international working group definitions [13]. In line with international recommendations for ITP, a bone marrow smear biopsy was performed in patients >60 years old and in patients not responding to CSs or IVIGs [14]. SLE was defined according to international guidelines (ACR) [15]. APS was defined according to the revised Sapporo criteria [16]. We ascertained age, gender, date at diagnosis of SLE and ITP and previous medications used for managing thrombocytopenia, including the duration of high-dose CS use and number of IVIG infusions. Bleeding severity at the time of diagnosis was evaluated by a standardized bleeding score with censored data for age [17]. We reviewed laboratory results, including complete blood counts at diagnosis and lowest platelet count and autoantibodies (ANA and presence of aPLs: aCL, anti-β2-glycoprotein 1 antibody and lupus anticoagulant). For TPO-RAs, we reviewed the type, date of commencement, duration, dose, side-effects and reason for interruption and therapeutic switch. Response (R) and complete response (CR) were defined according to standardized international criteria (CR: platelet count >30 × 109/l with at least a doubling of the baseline value or >100 × 109/l). Non-response (NR) was defined as absence of platelet count increase >30 × 109/l with at least a doubling of the baseline count or the need for rescue therapy (IVIGs and/or CSs) [13]. Literature review We searched MEDLINE via PubMed for all articles published between 2000 and 2017 by using the MeSH terms: Immune Thrombocytopenia (ITP) and Systemic Lupus Erythematosus (SLE), Romiplostim or Eltrombopag and Systemic Lupus Erythematosus. We found 247 articles and selected 13 describing 28 patients with SLE-ITP treated with TPO-RAs: 15 patients from 12 case reports [18–29], and 13 patients from a cohort of patients with secondary ITP treated with TPO-RAs [30]. Results Characteristics of ITP patients A total of 18 patients (14 females, 78%) with definite SLE according to ACR criteria were included in the study. Patient characteristics and results are summarized in supplementary Table S1, available at Rheumatology online. ITP preceded SLE diagnosis for 3 patients, was simultaneous with SLE diagnosis for 3, and occurred during the course of SLE for 12. Ten (55%) patients had aPLs, five (27%) with definite APS. The mean platelet count at ITP diagnosis was 36 × 109/l (range: 3–79×109/l), with severe bleeding manifestations in three patients. All patients received CSs and HCQ. Besides these drugs, patients received a median of 4 (interquartile range: 3–5) previous treatment lines for ITP before the start of TPO-RAs; 13 had received rituximab, and 7 underwent splenectomy. All but one patient (with an intracranial haemorrhage) had a least a platelet count <30 × 109/l before the start of TPO-RAs. The median age was 52 years (range: 21–70 years) at TPO-RA initiation. Six patients (33%) received romiplostim, five (28%) eltrombopag and seven (39%) both sequentially. Outcome Platelet response All but one patient achieved a response with TPO-RAs overall (94%), 12/13 (92%) with romiplostim (7 CR, 5 R) and 9/12 (67%) with eltrombopag (7 CR, 2 R). Eltrombopag was switched to romiplostim for seven patients because of related adverse events (n = 2, arthralgia and elevated liver enzyme levels), no response (n = 3) or relapse (n = 2). The median delay of response was 30 days for romiplostim (range: 14–35 days) and 17.5 days for eltrombopag (range: 7–30 days). After a median follow-up of 14.7 months (interquartile range: 4.7–47.5 months) with TPO-RAs, 11/18 patients (61%) had CR, 6/18 (33%) had R, and 1/18 (6%) had no response. Two patients who received eltrombopag presented relapse after an initial CR, after 7 and 20 months, respectively. One patient who received eltrombopag showed a sustained response after stopping TPO-RAs (6 months of follow-up after discontinuation). Two patients received a short course of TPO-RAs before surgery. Safety After a median follow-up of 14.7 months (interquartile range: 4.7–47.5 months) with TPO-RAs, 8/18 (44%) patients experienced one or more adverse events during treatment: two presented arthralgia and one elevated liver enzyme concentrations. Five patients (28%) showed thrombotic events (TEs) as a side-effect (Table 1) during treatment with eltrombopag (n = 4) or romiplostim (n = 1). TEs occurred at a median of 3.5 months (range: 1–7 months) after treatment. The platelet count at the time of TE was >150 × 109/l for three patients (range: 166–484 × 109/l). Table 1 Characteristics of patients with SLE-ITP who received TPO-RAs and presented TEs Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV aβ2GP1: anti-beta-2-glycoprotein 1; CR: complete response; F: female; LMVH: low-molecular-weight heparin; LA: circulating anticoagulant; M: male; NR: no response; NS: not specified; R: response; RTX: rituximab; SLE-ITP: SLE-associated immune thrombocytopenia; TE: thrombotic event; TPO-RA: thrombopoietin-receptor agonist. Table 1 Characteristics of patients with SLE-ITP who received TPO-RAs and presented TEs Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV Age, years/sex Previous therapies for ITP and SLE APS/aPLs Type of TPO-RAs Dose Response Type of TE Antithrombotic treatment at the occurrence of TE Duration of TPO-RA exposure at TE onset Platelet count at TE (× 109/l) Management of TPO-RA/TEs 52/F HCQ, CS, AZA, IVIG, RTX APS aCL + LA Obstetrical events Avatrombopag Eltrombopag Romiplostim NS 75 mg 4 µg/bw CR CR CR Stroke Aspirin 5 100 Avatrombopag continued LVMH, then warfarin and clopidogrel 28/F CS, HCQ, AZA, MMF, IVIG, RTX, CYC APS aCL + aβ2GP1 Arterial and venous events Eltrombopag Romiplostim 75 mg 3 µg/bw CR CR – Myocardial infarction Aspirin (warfarin withdrawn for 1 month) 1 484 Romiplostim withdrawn Aspirin, clopidogrel and warfarin 24/F HCQ, CS, MMF, AZA, IVIG, dapsone, RTX – Romiplostim 9 µg/bw CR Intracranial sinus thrombosis None 1 166 Romiplostim withdrawn LMWH Pulmonary embolism Non-compliance with LMWH 12 186 LMWH, then warfarin 60/F HCQ, CS, MMF, IVIG, RTX aPLs aCL Eltrombopag 75 mg CR Myocardial infarction None 10 94 Eltrombopag withdrawn Aspirin and clopidogrel 67/F CS, HCQ, AZA, RTX, splenectomy APS LA + aβ2GP1 obstetrical and venous events Eltrombopag 50 mg CR Catastrophic APS Rivaroxaban 6 269 Eltrombopag withdrawn Aspirin and UFH, plasma exchange, CS, IGIV aβ2GP1: anti-beta-2-glycoprotein 1; CR: complete response; F: female; LMVH: low-molecular-weight heparin; LA: circulating anticoagulant; M: male; NR: no response; NS: not specified; R: response; RTX: rituximab; SLE-ITP: SLE-associated immune thrombocytopenia; TE: thrombotic event; TPO-RA: thrombopoietin-receptor agonist. Four arterial TEs occurred in four patients who received eltrombopag, with previous APS in three, and with aPL positivity without definite APS in the last patient. The arterial TEs were two myocardial infarctions, one stroke and one catastrophic APS (CAPS). CAPS occurred 6 months after TPO-RA initiation in a 67-year-old woman during rivaroxaban treatment, with good adherence to treatment. The woman presented multiple cerebral strokes, skin necrosis and myocardial infarction. The outcome was favourable, with immediate eltrombopag cessation, anticoagulation therapy, high-dose CSs, plasma exchange and IVIGs. The two other patients with APS had received aspirin before the event. Two venous TEs (pulmonary embolism and, a year later, intracranial sinus thrombosis) occurred in a 24-year-old woman (without APS or aPL positivity) who received romiplostim. She had been under low-molecular-weight heparin treatment for 1 year when the second event occurred but had stopped the treatment at this time (non-compliance). In all but one patient with TEs, TPO-RAs were immediately discontinued at the time of the TE. However, because of ITP relapse, TPO-RAs were reinitiated in threee patients receiving anticoagulation or anti-platelet therapy, with a median follow-up of 7 months (range: 1–24 months). The TPO-RA was definitely stopped in the patient with CAPS. No SLE flare was observed in patients exposed to TPO-RAs. Systematic literature review The literature included reports of 15 patients with SLE-ITP [12 females; median age 44 years (14–69)]; 14 (93%) achieved overall response (R + CR) with TPO-RAs (Table 2). In all, eight patients (53%) had received eltrombopag and seven (47%) romiplostim. Two venous TEs (7%) were reported, in one patient with aPLs (deep vein thrombosis) and in one with APS despite warfarin treatment and an INR above the target, with a fatal result [25]. CAPS occurred in a young patient who received romiplostim for 11 weeks, revealing SLE and APS. The outcome was favourable with romiplostim cessation, anticoagulation treatment, CSs and rituximab [21]. A patient presented a thrombotic microangiopathy after romiplostim treatment [18]. In a group of patients with various auto-immune diseases, including SLE-ITP and APS, Gonzáles-Lópes et al. [30] reported an incidence of 10% of TEs. In their study, two out of six patients with APS developed TEs (superficial phlebitis and pulmonary embolism) [30]. A stroke occurred in one patient with SLE-ITP, with no more details in the review [30]. Table 2 Literature review of 15 case reports describing the use of TPO-RAs for SLE-ITP Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Aba: abatacept; aβ2GP1: anti-beta-2-glycoprotein 1; AVK: antivitamin K; CR: complete response; Elt: eltrombopag; F: female; M: male; NR: non-response; NS: not specified; Romipl: romiplostim; RTX: rituximab; R: response; SLE-ITP: SLE associated immune thrombocytopenia; Spl: splenectomy; Toci: tocilizumab; TPO-RA: thrombopoietin-receptor agonist. Table 2 Literature review of 15 case reports describing the use of TPO-RAs for SLE-ITP Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Reference Age, years Sex Previous treatments aPLs (type of event if APS) Antithrombotic treatment TPO-RA Dose Response Time to response (days) Side-effects Platelet count at TE/delay Magnano et al. 1 69 F CS, IVIG, Spl, RTX None None Eltrombopag 25 mg CR 14 None – 2 39 F CS, IVIG, CYC, AZA, RTX None None Romiplostim 7 µg/bw CR 14 None – Gonzalez-Nieto 44 M CS, IVIG, CYC, AZA, RTX LA (arterial event) NS Romiplostim 2 µg/bw CR 21 None – Alkaabi 34 F CS, IVIG, RTX, CYC Aβ2GP1 NS Romiplostim 3 µg/bw CR 6 None – Tomov 19 F CS, IVIG, RTX None None Romiplostim UK CR NS Renal thrombotic microangiopathy 60×109/l at 42 days Borrell 72 F CS, MMF, IVIG, RTX, Spl aCL, aβ2GP1 None Romiplostim UK CR NS Left popliteal deep vein thrombosis 177×109/l at 90 days LaMoreaux 14 M CS, IVIG, RTX, Spl aCL, LA None Romiplostim UK CR NS Catastrophic APS 111×109/l at 77 days Cela 55 F CS, RTX, CSA NS None Eltrombopag 50 mg CR 14 None – Gudbrandsdottir NS NS NS NS NS NS UK NR – NS – Maroun 1 44 F CS, IVIG, HCQ aCL None Eltrombopag UK CR 21 None – 2 46 F HCQ, CS None Aspirin Eltrombopag 50 mg CR 7 Urticaria – 3 51 F CS, IVIG, RTX None None Eltrombopag 50 mg CR NS None – Scheinberg 30 F CS, CYC, AZA, IVIG, RTX NS None Eltrombopag 50 mg CR 3 None – Boulon 61 F CS, IVIG, AZA, CYC, Spl LA (obstetrical and venous events) AVK Eltrombopag 50 mg CR 30 Pulmonary embolism 119×109/l at 30 days Martínez 39 F CS, HCQ, MMF, AZA, RTX NS None Eltrombopag 50 mg CR 30 None – Aba: abatacept; aβ2GP1: anti-beta-2-glycoprotein 1; AVK: antivitamin K; CR: complete response; Elt: eltrombopag; F: female; M: male; NR: non-response; NS: not specified; Romipl: romiplostim; RTX: rituximab; R: response; SLE-ITP: SLE associated immune thrombocytopenia; Spl: splenectomy; Toci: tocilizumab; TPO-RA: thrombopoietin-receptor agonist. Discussion TPO-RAs have increased in use as second-line therapy for ITP. However, their safety has been evaluated mostly in primary ITP. We have few reports describing their use in SLE-ITP. This is the largest real-life study of patients with SLE-ITP treated with TPO-RAs. We demonstrated the drugs’ efficacy in patients with previously failure or relapse after standard therapy. The rate of response overall (90%) was very high. These results are in line with those in the literature, finding 82% response (23 of 28 cases reported [16–27] or cohort cases [30]); five patients (8%) did not achieve response. The recent Spanish cohort of secondary ITP treated with eltrombopag showed that immune- and infection-related ITP was more prone to respond to TPO-RAs than ITP secondary to neoplasia [30]. However, in addition to commonly reported adverse events, such as arthralgia and increased liver enzyme concentrations, 28% of our patients showed serious unexpected TEs, including venous and arterial thrombosis. Strikingly, four of five of these patients had APS (n = 3) or aPLs (n = 1). Four venous TEs have been reported in the literature, in patients with APS. One stroke was reported in a patient with SLE-ITP [30]. Moreover, three cases of CAPS in patients exposed to TPO-RAs, including ours, occurred in two patients with SLE associated with APS and one with primary APS [21]. It is interesting to note that we observed a CAPS on rivaroxaban, because TEs have been previously reported on direct oral anticoagulant therapy, suggesting that direct oral anticoagulant therapy should not be used in APS patients [29, 30]. These life-threatening events are per se a signal to use TPO-RAs with caution in patients with SLE and APS. The cumulative incidence of TEs was ∼5% in the two pivotal prospective trials, but they are more likely to occur in older patients; however, patients with a definite APS were excluded from these trials [19, 22]. In ITP, increased risk of TEs has been related to splenectomy, age and co-morbidity [25], but TPO-RAs may be intrinsically associated with TEs. The pathogenesis is still unclear, because both venous and arterial thrombosis occurs independently of platelet count and at any time during treatment. Indeed, a study suggested that platelets were activated with TPO-RA treatment [31]. Our study has some limitations owing to its retrospective design, including some potential selection bias and the low number of patients, but prospective trials of SLE patients exposed to TPO-RAs would be difficult to perform. 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RheumatologyOxford University Press

Published: May 10, 2018

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