SLE dengan Trombositopenia -- Winni.pptx

SLE dengan Trombositopenia - Winni.pptx

1. Journal reading Winni Aprillia Putri Dr. dr. Awalia , Sp.PD , K-R

2. Introduction In 1933 and 1934 thrombocytopenia was recognized to be associated with SLE. Thrombocytopenia; typically clusters with other haematological manifestations such as autoimmune haemolytic anaemia ( more frequent in patients with severe than mild thrombocytopenia) and leukopenia; is characterised by a platelet count (PC) <100 × 10^9 (observed in 10%-40% of SLE patients) . PC less than 20,000 μl-1 are termed severe thrombocytopenia in SLE ( relatively uncommon) , those between 20 and 50,000 μl-1 are considered moderate and those over 50,000 μl-1 are called mild thrombocytopenia. Thrombocytopenia in SLE is reported to be an independent predictor of mortality and contributes to morbidity and increased damage. Pietto MCB, Lev PR, Glembotsky AC, et al. Pathogenic mechanisms contributing to thrombocytopenia in patients with sy st emic lupus erythematosus Pathogenic mechanisms contributing to thrombocytopenia in patients with systemic lupus erythematosus. Platelets . 2022;33(5):743-754. doi:10.1080/09537104.2021.1988547 Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

3. Thrombocytopenia is a prevalent clinical symptom of systemic lupus erythematosus (SLE), reported in roughly onethird to half of all patients and part of the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) 2012, Revised ACR guideline 1997, and the 2019 (EULAR/ACR) classification criteria.

4. …bleeding The true incidence of serious bleeding in lupus-associated thrombocytopenia remains unknown. Currently, the severity of thrombocytopenia is determined based on the PC and the assumption that the severity of bleeding increases as the PC decreases. In the context of thrombocytopenia, cutaneous and visible mucosal bleeds are considered minor bleeds, while all other bleeds are major bleeds. In the INSPIRE cohort, major bleeding was observed in only 1 patient among 22 patients with severe thrombocytopenia, 9 patients had minor bleeding, and the rest had no visible bleeding. The risk of bleeding is increase significantly in individuals aged >60 years with a history of haemorrhage. The degree of thrombocytopenia is strongly associated with the severity of hemorrhagic complications; grade II (GI or genitourinary) and grade III (CNS and pulmonary) bleeds were seen in 15% of patients with a PLT count of 50,000 - 100,000, 11% in those with a PLT count of 20,000-50,000, and 42% of those with PLTs less than 20,000. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

5. Pathogenesis of Thrombocytopenia in SLE The most common mechanism is believed to be peripheral PLT clearance via anti-PLT antibodies, similar to ITP . Excessive plt destruction and/or reduced production from megakaryocytes are considered major factors contributing to SLE-associated thrombocytopenia. Platelet production involves a complex sequence of events that drive undifferentiated hematopoietic progenitors through 2 well individualized processes, megakaryopoiesis and thrombopoiesis. Megakaryopoiesis takes approximately 4–7 days. Platelet apoptosis and loss of sialic acid from platelet glycoproteins are contributing mechanisms of peripheral clearance, while inhibition of proplatelet formation is the main pathway interfering platelet production in the bone marrow, overall leading to decreased platelet counts. Pietto MCB, Lev PR, Glembotsky AC, et al. Pathogenic mechanisms contributing to thrombocytopenia in patients with sy st emic lupus erythematosus Pathogenic mechanisms contributing to thrombocytopenia in patients with systemic lupus erythematosus. Platelets . 2022;33(5):743-754. doi:10.1080/09537104.2021.1988547 Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406 N ormal megakaryocyte and proplatelet production N ormal peripheral platelet clearance. M egakaryopoiesis is increased, while thrombopoiesis is inhibited In peripheral blood, platelet clearance is increased through different mechanisms including apoptosis, desialylation and activation.

6. Pathogenesis of Thrombocytopenia in SLE These picture suggest that c- Mpl Abs block TPO signaling and resulting in inhibition of megakaryogenesis in the BM. Indeed, c- Mpl Abs from SLE patients were shown to block TPO ligation to c- Mpl ; confirming their pathogenic role in MK hypoplasia.

7. Pathogenesis of Thrombocytopenia in SLE Pietto MCB, Lev PR, Glembotsky AC, et al. Pathogenic mechanisms contributing to thrombocytopenia in patients with sy st emic lupus erythematosus Pathogenic mechanisms contributing to thrombocytopenia in patients with systemic lupus erythematosus. Platelets . 2022;33(5):743-754. doi:10.1080/09537104.2021.1988547 Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406 Jiang Y, Cheng Y, Ma S, Li T, Chen Z, Zuo X. Systemic lupus erythematosus-complicating immune thrombocytopenia : From pathogenesis to treatment. 2022;132(July).

8. Pathogenesis of Thrombocytopenia in SLE Other mechanisms for thrombocytopenia in SLE include decreased production via antibody- or T-cell-mediated suppression of megakaryocytes, thrombotic microangiopathy, macrophage activation syndrome and hypersplenism. The association between Antiphospholipid antibody (APLA) and thrombocytopenia has been well documented in medical literature and is considered an antiphospholipid syndrome (APS) non-criteria manifestation. Antiphospholipid antibodies cause thrombocytopenia; however, thought to be related to platelet lysis, reduced platelet synthesis and increased platelet pooling. Destruction of platelets can be either immune-mediated or thrombotic microangiopathy, namely catastrophic antiphospholipid syndrome (CAPS). Pietto MCB, Lev PR, Glembotsky AC, et al. Pathogenic mechanisms contributing to thrombocytopenia in patients with sy st emic lupus erythematosus Pathogenic mechanisms contributing to thrombocytopenia in patients with systemic lupus erythematosus. Platelets . 2022;33(5):743-754. doi:10.1080/09537104.2021.1988547 Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406 Jiang Y, Cheng Y, Ma S, Li T, Chen Z, Zuo X. Systemic lupus erythematosus-complicating immune thrombocytopenia : From pathogenesis to treatment. 2022;132(July).

9. Management In principle, thrombocytopenia with PC >50.000 does not generally require specific therapy unless subjects are symptomatic and/or other organ manifestations coexist that merit therapeutic intervention. The treatment algorithms for thrombocytopenia in SLE either from the overall SLE disease management protocols or extrapolated from the ITP treatment recommendations. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406 Immunosuppressive Therapy IVIg Rituximab Belimumab TPO Receptor Agonists (TPO-RA) Spleen Tyrosine Kinase (SYK) Inhibitor Platelet Transfusion Splenectomy The goal of current treatment of SLE-ITP is to stop active bleeding, induce SLE remission, and reduce the risk of future bleeding.

10. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406 Jiang Y, Cheng Y, Ma S, Li T, Chen Z, Zuo X. Systemic lupus erythematosus-complicating immune thrombocytopenia   : From pathogenesis to treatment. 2022;132(July).

11. Immunosuppressive Therapy CS are considered the 1st-line treatment b ecause of the pathogenesis of thrombocytopenia in SLE, which is immune system-mediated . Among various formulations, dexamethasone and prednisolone are extensively used. In a study, 91% of patients with SLE-thrombocytopenia had either antiGPIIb /IIIa or anti-TPO-R antibodies, and 18.7% of patients had both antibodies. Patients with SLE who have positive anti-TPO-R antibodies had much greater MK hypoplasia and a poorer response to immunoglobulin (IVIg) and corticosteroids. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

12. Immunosuppressive Therapy American Society of Hematology (ASH) recommends either prednisone (0.5–2.0 mg/kg/day) or dexamethasone (40 mg/day for 4 days) as the initial therapy in newly diagnosed adult patients with ITP. The EULAR guidelines recommend initial treatment with pulse methylprednisolone followed by 0.5–0.7 mg kg/day, prednisone equivalent. Thrombocytopenia responds well to corticosteroids; however, treatment is often lengthy and characterised by relapses of steroid tapering or stopping. Although equivalent doses of both formulations were effective, there were few differences between them. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

13. IMMUnosupressants IV pulse cyclophosphamide was effective in 7 cases refractory to splenectomy and steroids or those requiring excessive doses of steroids. Limited success has been reported with azathioprine, cyclosporine, dapsone, vincristine, and mycophenolate.

14. IVIg The preferred alternative in situations, where CS are contraindicated or steroid-sparing alternatives and in refractory patients. It was found that thrombocytopenia did not improve with low-dose IVIg (0.5 g/kg). IVIg at a dose of 2 g/kg was administered for a variety of clinical symptoms, including SCLE, discoid lupus erythematosus, LN, haematological (haemolytic anaemia, thrombocytopenia and pancytopenia) and NP-lupus. In individuals with symptomatic ITP who had not received treatment before, an RCT examined the effects of prednisone alone, IVIg alone and a combination of the two. The results showed responses in 82%, 54% and 92% of patients, respectively. No difference was observed between the IVIg and prednisone groups, and IVIg offered no advantage over prednisolone as the primary therapy. Relapse was also not statistically significant between groups. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

15. Rituximab Considering the pathophysiological mechanisms underlying SLE and the depletion of B cells is an attractive option. this medication may remain a viable option, particularly in younger patients with uncontrolled ITP and a previous transient complete response to steroids. RTX has become the first choice of second-line treatment for primary ITP. RTX was administered intravenously once weekly at a dose of 375 mg/m2 for a total of four times. The use of rituximab in SLE is based on observational studies; however, it has been well-studied in chronic ITP. Among the 44 patients with thrombocytopenia, the overall response rate was 91%. Rituximab is effective in treating a number of SLE symptoms, including thrombocytopenia, neurological symptoms, cutaneous lupus, arthritis and neurological manifestations (30.3%, 24.2% and 15.2%, respectively). Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

16. Belimumab Established as an effective and safe drug for the treatment of SLE. Permit glucocorticoid tapering, but it also reduces disease activity and flares in several SLE domains, thereby limiting damage. Additionally, it has demonstrated efficacy in APL-associated thrombocytopenia. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

17. TPO Receptor Agonists (TPO-RA) FDA has approved 2 TPO agonists for use in refractory ITP, eltrombopag and romiplostim . Both attach to the TPO-R, changing its structure and initiating the JAK-2/signal transducer and activator of transcription (JAK2/STAT5) pathway, which increases platelet production and megakaryocyte progenitor cell proliferation. Romiplostim acts on surface receptors, thereby competing with endogenous TPO, whereas eltrombopag binds the transmembrane domain of the receptor. Compared with primary ITP, the risk of infection in patients with SLE is much higher, as almost all treatment strategies for SLE include immunosuppressants. Rebound thrombocytopenia after stopping TPO-RA was observed in most patients; however, in only 10% of patients, the PC dropped below the pretreatment level Arterial and venous thromboembolisms were observed with incidence of thromboembolism events includes 4.1–7.5/ 100 patient-years for romiplostim and 3.4/ 100 patient years for eltrombopag . These thromboembolic events were not associated with either the dose of TPO-RA or the degree of thrombocytosis. By this corollary, TPO-RA should be avoided in SLE with APS. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

18. Spleen Tyrosine Kinase (SYK) Inhibitor In individuals with ITP, phagocytosis-based antibody mediated platelet destruction is largely dependent on SYK activation. Fostamatinib inhibits platelet phagocytosis mediated by autoantibodies and suppresses SYK activation in macrophages. The US FDA has approved fostamatinib for the treatment of refractory chronic ITP. Fostamatinib at 100 mg twice daily was more effective than placebo in terms of the overall response rate (43% vs. 14%). Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

19. Platelet Transfusion Platelet infusion, either pooled or concentrated, is not recommended unless life-threatening bleeding occurs. The role of splenectomy in the treatment of SLE thrombocytopenia remains a matter of debate. Several authors have reported that it may be less effective in SLE than in ITP, and that a significantly higher rate of cutaneous vasculitis and serious infections occur in patients with SLE who undergo splenectomy. The spleen is the major site of platelet destruction and the resident site of long-lived plasma cells. Splenectomy removes the primary site of platelet clearance and autoantibody production. Splenectomy Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

20. Pregnancy-Related Thrombocytopenia Management: Special Considerations Pregnancy can increase lupus activity, and flares during any trimester. Up to 76% of all causes, gestational thrombocytopenia is the most frequent cause of thrombocytopenia in pregnancy. The PC will often stay between 130,000 and 149,000 μl−1, have minimal effect on the health of the mother and resolve on its own following delivery. Pregnant women with SLE with thrombocytopenia are at increased risk of miscarriage, intrauterine stillbirth and preterm delivery, gestational thrombocytopenia, pre-eclampsia/ Hemolysis , Elevated Liver enzyme levels, and Low Platelet levels (HELLP) syndrome and acute fatty liver of pregnancy compared to those without thrombocytopenia. 1st-line treatment included either oral corticosteroids or IVIg. Among the various formulations of corticosteroids, prednisolone is preferred as it does not cross the placenta. In refractory cases, azathioprine and cyclosporin A have better safety profiles. However, these medications have a delayed response time with response rates of 40–60%. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

21. Pregnancy-Related Thrombocytopenia Management: Special Considerations Rituximab crosses the placenta and suppresses neonatal B-lymphocyte development, causing prolonged lymphopenia in newborns. Although the current literature indicates that the real incidence of neonatal infection following maternal rituximab administration is minimal, there is an elevated risk of infection in both the mother and the newborn. – Similarly, TPO-RA such as eltrombopag has been successfully tried in several reports. Although platelet transfusion is normally not advised because of the short-term benefits of quick clearance, it can be taken into consideration in the event that an emergency caesarean section is necessary. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

22. Prognosis Mortality is considerably lower in complete remission from thrombocytopenia. (INSPIRE) cohort, the death rate for individuals with severe thrombocytopenia is >3x than moderate thrombocytopenia and controls. Patients with moderate-to-severe thrombocytopenia had also a higher hospitalisation rate. Multiple studies have reported correlations between thrombocytopenia and increased disease activity, disease severity, as well as kidney and CNS involvement in SLE. Kumar A, Shobha V. Management of Thrombocytopenia in SLE. Published online 2024. doi:10.1177/09733698241281406

23. Conclusion Severe thrombocytopenia is uncommon in SLE and does not result in severe bleeding. It responds to steroid treatment briskly but may relapse despite concomitant steroid-sparing therapy. Rituximab and IVIG are useful in patients with refractory disease. Non-immunosuppressive agents such as TPO-RA are useful adjuncts in refractory thrombocytopenia; however, their use must be restricted to patients with nonAPS and for a short duration until the PC is >30.000.

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