Sequential treatment using low-dose rituximab and belimumab for thrombotic microangiopathy with systemic lupus erythematosus

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The treatment of TMA often requires immunosuppressive agents, high-dose corticosteroids and plasma exchange (PEX). Both rituximab (RTX) and belimumab (BEL) target B cells. The combination of RTX and BEL has recently been used for refractory and severe organ involvement in systemic lupus erythematosus. However, the clinical outcome of patients with TMA and SLE treated with sequential therapy between RTX and BEL remains elusive. Case Series: We reported 2 patients who were diagnosed with SLE with TMA and were administered a combination treatment of high-dose corticosteroids, immunoglobulin, and PEX at the initial stage. No improvements in microangiopathic anaemia, thrombocytopenia, or renal failure were observed. Low-dose RTX was administered in both patients, and both patients responded well. BEL was utilized to rapidly reduce the reliance on these agents and prevent the relapse of SLE at the maintenance stage. Ultimately, 2 patients fully recovered with an SLE Disease Activity Index score of 0, and prednisolone was stopped without relapse. Conclusion Sequential treatment with low-dose RTX and BEL could be an encouraging approach for the treatment of TMA in patients with SLE and rapid glucocorticoid reduction. Thrombotic microangiopathy systemic lupus erythematosus rituximab belimumab Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the involvement of various organs and tissues due to the binding of self-antibodies and immune complex formation [ 1 ]. The pathological manifestations of SLE include the deposition of immune complexes and vasculitis. Clinically, multiple organs are often affected, and the levels of specific antibodies in the serum are elevated. Thrombotic microangiopathy (TMA) syndrome is a potentially life-threatening complication and is defined as an integrated syndrome of microangiopathic haemolytic anaemia, thrombocytopenia, and organ injury[ 2 ]. SLE is a major underlying cause of secondary TMA. According to reports, the incidence of SLE complicated with TMA ranges from 1–4% [ 3 – 5 ], with a mortality rate as high as 33.3–62.5%[ 2 – 9 ]. Currently, there is no standardized treatment protocol available for the management of SLE complicated with TMA[ 10 ]. We reported two patients with TMA with SLE who showed good efficacy and prognosis with sequential treatment with rituximab (RTX) and belimumab (BEL). Patient 1: A 12-year-old girl presented with a 7-day history of gradually progressive bilateral lower extremity weakness, a sallow complexion and a 5-day history of fever in December 2020. The laboratory data revealed proteinuria, haematuria, pancytopenia, acute kidney injury, hypoproteinaemia, and decreased C3 and C4 levels. High titres of antinuclear antibody (ANA) and positive anti-double-stranded DNA and anti-Smith antibodies were detected. Lactic dehydrogenase (LDH) was also elevated. Lupus anticoagulant, ACL antibody, and anti-b2GP1 antibody levels and Coombs test results were all negative (Table 1). She was diagnosed with SLE. Her SLE Disease Activity Index (SLEDAI) was 24, indicating high disease activity; therefore, she was initially treated with 3 pulses of 1000 mg (20 mg/kg) intravenous methylprednisolone per day followed by intravenous methylprednisolone 48 mg per day, 20 g/day (total of 3 doses, 1 g/kg) intravenous immunoglobulin infusions and 100 mg oral hydroxychloroquine (HCQ) twice a day (3.4 mg/kg). The platelet concentration increased from 30x10 9 /L to 208x10 9 /L and then quickly decreased to 42x10 9 /L. Her creatinine increased from 124 µmol/L to 208 µmol/L and then decreased to 166 µmol/L, and her peripheral blood showed numerous schistocytes and increased lactate dehydrogenase (LDH). The patient had no history of diarrhoea, bloody stools, neuropsychiatric symptoms, or organ transplantation. Stool routine tests, coagulation function tests, pneumococcal antigen tests and magnetic resonance imaging of the brain were all negative. Based on these findings, refractory SLE and lupus nephritis with TMA were diagnosed. Despite the initial improvement, her anaemia, thrombocytopenia and renal failure recurred. PEX was performed once daily for 3 days. However, the patient’s condition failed to improve. RTX (100 mg) was administered intravenously (1 dose every 2 weeks; a total of 2 doses), along with cyclophosphamide (800 mg/m 2 , a total of 8 doses). After 2 doses of RTX, PLT and serum creatinine levels returned to normal. Despite follow-up laboratory examinations, which showed that her PLT and serum creatinine levels remained normalized and that her Hb gradually increased to normal levels, the patient still had proteinuria. Therefore, intravenous BEL (10 mg/kg) and oral mycophenolate mofetil (MMF, 1 g/day) were prescribed. She was maintained on BEL, MMF (1 g per day) and HCQ (0.2 g per day), and her prednisolone treatment was stopped in April 2023, with an SLEDAI score of 0. She developed upper respiratory syndrome twice during the follow-up, and these conditions were cured by symptomatic treatment. At the last visit, the patient was maintained with BEL, HCQ and MMF and had no relapse. Patient 2: A 12-year-old girl with a 1-week history of fever, a 5-day history of polyarthritis and a 4-day history of haematuria and oedema was admitted to our centre in December 2021. Routine blood tests revealed thrombocytopaenia, anaemia and an elevated reticulocyte count. Urine tests revealed albuminuria and haematuria, with an elevated 24-hour urine protein level (24hUPro). Peripheral blood and bone marrow smears showed numerous schistocytes. ANA and anti-double-stranded DNA were positive, and decreased C3 and C4 levels were observed. Lupus anticoagulant, ACL antibodies, anti-b2GP1 antibodies and Coombs tests were all negative (Table 1). The patient had no history of diarrhoea, bloody stools, neuropsychiatric symptoms, or organ transplantation. Stool routine tests, coagulation function tests, pneumococcal antigen tests and magnetic resonance imaging of the brain were all normal. She was treated with intravenous methylprednisolone 48 mg per day. Oral HCQ (100 mg) was prescribed twice per day. The PLT initially improved from 80 x10 9 /L to 122x10 9 /L. Renal biopsy was performed to evaluate her renal dysfunction. We detected IgA(++), IgG(+++), C3(+++), Fib(+), IgM(+), and C1q(+++) using immunofluorescence. Under light microscopy, a total of 13 glomeruli were observed, and the findings were as follows: moderate-severe diffuse proliferation of the mesangial matrix, diffuse endocapillary hypercellularity composed of swollen endothelial cells, leukocytes, irregularly thickened glomerular capillary wall segments, double track changes, capillary lumen stenosis, and scattered thrombosis. ADAMTS13 inhibitor and antifactor H autoantibodies were negative. The patient also underwent whole-exon gene sequencing, which revealed that the proband had heterozygous mutations in DNASE1 (c.653T > A, p.I218N, Chr16:3707291). We did not find any gene markers related to TMA recurrence. SLE with TMA was diagnosed, and haematological recovery was observed after she was treated with 2 pulses of 500 mg methylprednisolone (10 mg/kg) per day for 3 days followed by 60 mg/day oral prednisolone (1 mg/kg). Despite the initial improvement, thrombocytopenia, anaemia, and increased LDH and serum creatinine levels recurred. Treatment with high-dose corticosteroids was interrupted because of CMV infection. Intravenous immunoglobulin infusions of 20 g/day (total of 3 doses, 1 g/kg) along with PEX were performed once daily for 5 days and then every two days 5 times. However, the patient’s condition failed to improve. A total of 100 mg RTX per 2 weeks with 800 mg cyclophosphamide (500 mg/m 2 ) was administered to this patient when the CMV infection was cured. PLT and serum creatinine levels returned to normal after 3 doses of RTX and 1 dose of cyclophosphamide. Treatment with cyclophosphamide was interrupted because of a gastrointestinal reaction. Intravenous BEL (10 mg/kg) and oral MMF (1 g/day) were administered because of persistent gross haematuria and moderate levels of proteinuria. She developed upper respiratory syndrome once during the follow-up, which was resolved by symptomatic treatment. At the last visit, the patient had been maintained with BEL, HCQ and MMF. Table 1 Clinical and laboratory baseline data of the 2 patients Item Patient 1 Patient 2 Reference range Race/Ethnicity Yellow race/The Han nationality Yellow race/The Han nationality - Age/Gender 12/F 12/F - Weight (kg) 59 62 Body surface are (m 2 ) 1.63 1.69 Fever - - - Rash - - - Oral ulcers - - - Nonscarring alopecia - + - Arthritis - + - Serositis + + - Neurologic - - - ESR (mm/h) 2 22 0-20 CRP (mg/L) 0.9 0.5 0-8 White blood cells (x 109/L) 3.44 3.94 4-10 Haemoglobin (g/L) 62 80 115-150 Platelets (x 10 9 /L) 30 108 100-300 Reticulocyte proportion (%) 8.4 3.5 0.5-2.2 TBil (mmol/L) 12.15 5.06 3.5-23.5 DBil (mmol/L) 1.65 0.83 0.5-6.5 ALT (U/L) 19 43 7-40 AST (U/L) 25 28 13-35 Albumin (g/L) 29 23.2 40-55 Serum creatinine (umol/L) 124 97 40-105 Lactate dehydrogenase (U/L) 633.1 516 120-250 24hUPro (g) 4.68 9.8 ＜0.15 Urine erythrocytes (/HPF) 23.8 1769.3 0-3 D-Dimer (mg/L) 1.5 2.07 0-0.5 PT (seconds) 11.4 7.12 9.2-12.5 APTT (seconds) 23.9 29.8 25.1-36.5 Fibrinogen (g/L) 1.63 2.61 2.0-4.0 ANA 1:1000 1:1000 ＜1:100 Anti-dsDNA antibody (IU/ml) 204.3 302.89 0-100 Anti-Smith antibody (IU/ml) 40 7.7 0-20 Anti-SSA antibody (IU/ml) 10.3 5.54 0-20 Anti-SSB antibody (IU/ml) 8.45 5.1 0-20 LA 0.95 1.06 0.92-1.20 ACL antibodies (CU) 1.7 2,7 0-20 Anti-b2GPI antibodies IgG (CU) 13 8.9 0-20 C3 (g/L) 0.2 0.2 0.79–1.17 C4 (g/L) 0.02 0.06 0.1–0.4 Blood smear Schistocytes and reduced platelets Schistocytes and reduced platelets - Bone marrow biopsy Schistocytes and Schistocytes and - reduced platelets reduced platelets Abbreviations: ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; TBil, total bilirubin; DBil, direct bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 24hUPro, 24-h urine protein; PT, prothrombin time; APTT, activated partial thromboplastin time; ANA, anti-nuclear antibody; Anti-SSA, anti-Sjögren's syndrome A; Anti-SSB, anti-Sjögren's syndrome B; LA, lupus anticoagulant; ACL, anticardiolipin; Anti-b2GP1, anti-β2-glycoprotoein 1; C3, complement 3; C4, complement 4; IgG, immunoglobin G. Discussion TMA is less common but is a potentially lethal disease affecting small vessels. Classically, TMA presents with a triad of haemolytic anaemia, thrombocytopaenia, and ischaemic end-organ failure (most commonly, the kidneys). More commonly, TMA manifests as a secondary complication of other systemic diseases, often autoimmune diseases, including SLE [2.11]. The differential diagnosis of TMA in patients with SLE includes antiphospholipid antibody syndrome, thrombocytopenic purpura, complement-mediated and infection-associated haemolytic uraemic syndrome, drug-mediated TMA, and malignant hypertension [12]. Previous studies have reported that TMA is an independent risk factor for poor renal outcomes in patients with lupus nephritis, and patients with this condition may have an inadequate response to conventional therapy compared to those with lupus nephritis but without TMA, leading to a higher mortality rate [10.13-14]. Clinically, it can be challenging to differentiate TMA from fever, thrombocytopenia, and renal function impairment caused by lupus activity itself, which can complicate diagnosis and treatment decisions. Kidney biopsy can confirm renal microangiopathy[15]. However, when a kidney biopsy cannot be performed due to special circumstances, TMA can be indicated by specific laboratory indicators, such as a decrease in haemoglobin levels, a decreased platelet count, elevated LDH levels, the presence of fragmented red blood cells in the peripheral blood, and a negative Coombs test [16]. The laboratory examination of our 2 patients revealed a decrease in haemoglobin levels; a decrease in platelet count; an increase in LDH levels; the presence of fragmented red blood cells in the peripheral blood; and decreases in the Coombs test, ACL antibodies, and anti-b2GP1 antibodies; and decreased C3 and C4 levels. ADAMTS13 inhibitor and anti‑factor H autoantibodies were negative in Patient 2, and a renal biopsy was also performed in Patient 2, revealing histological findings of wire-loop lesions with double contours and the formation of microthrombi in glomerular capillaries. However, in Patient 1, kidney biopsy could not be performed initially due to the severity of the disease and the progressive decrease in PLT levels. Special medication, infection, organ transplantation and other medical history were excluded for the two patients presented in this study. Treatment for SLE with TMA includes high-dose corticosteroids, PEX, intravenous immunoglobulin infusions and immunosuppression therapy. Renal replacement therapy is needed for patients with progressive deterioration of kidney function or severe renal insufficiency[17-18]. Immunosuppression therapy for SLE patients with TMA includes corticosteroids, cyclophosphamide, and MMF [19]. The present study reported 2 patients who received high-dose corticosteroids, intravenous immunoglobulin infusions, and PEX at the initial stage. Both patients had recurrent thrombocytopenia, anaemia and increased serum creatinine levels. RTX is a human-murine chimeric anti-CD20 antibody that cankill target cells through antibody-dependent cytotoxicity, complement-dependent cytotoxicity or direct effects, inhibit excessive cytokine release, and reduce endothelial cell damage. The European League Against Rheumatism stated that RTX should be considered for treating organ-threatening, refractory lupus[20-21], and no guidelines for the treatment of TMA in patients with LN have been established. It has been reported that RTX is a standard treatment for relapsed and refractory TMA based on the excellent outcomes observed in patients who respond poorly to PEX and high-dose corticosteroids[22]. The optimal dose and schedule of RTX for TMA are unclear, but the most common approach is 375 mg/m 2 RTX once or twice per week for 4 to 8 weeks. The satisfactory efficacy of reduced-dose regimens of 100 mg weekly for 4 weeks has been demonstrated in a previous study[22]. In our report, Patient 1 was prescribed low-dose RTX (100 mg weekly for 2 weeks), and Patient 2 was prescribed low-dose RTX (100 mg weekly for 3 weeks). We chose this dose in consideration of the high cost and infection risk of RTX. Both patients responded well to low-dose RTX. BEL is a recombinant human IgG-1λ monoclonal antibody that inhibits the binding of B-cell activating factor (BAFF) to its receptor. Some studies have revealed that B-cell depletion with RTX leads BAFF overexpression[23]. An increase in BAFF levels after RTX may contribute to severe flares and could limit the effectiveness of RTX in some patients with SLE [21]. This finding provides a basis for the use of RTX sequentially with BEL therapy in SLE patients. The phase II SynBioSe study showed significant clinical and immunological improvements from baseline in patients with severe refractory SLE who received RTX followed by BEL and that patients maintained a response over two years [24]. The 2019 update of the EULAR recommendations for the management of SLE suggested that BEL is beneficial for tapering daily doses of glucocorticoids to acceptable levels (a maximum of 7.5 mg/d)[20]. S Hanai et al reported the case of a young girl who was diagnosed with TMA with refractory LN and who received RTX combined with BEL, which gradually improved the patient’s LN and TMA. Prednisone was tapered to 5 mg/day, and the patient experienced no recurrence for approximately 3 years [10]. Jun Liu et al reported that patients who were all diagnosed with thrombotic thrombocytopenia purpura with SLE received sequential treatment with RTX and BEL. All 4 patients recovered with an SLE Disease Activity Index score of 0 and reached the prednisolone dose goal of <7.5 mg/d without relapse[24]. We reported sequential therapy of BEL followed by RTX in patients with SLE with TMA who had good follow-up outcomes and no glucocorticoid doses. The most common adverse reaction to RTX is an infusion reaction, and the most common adverse reaction to BEL is infection. In a randomized controlled trial (NCT02260934), researchers showed that a combination of RTX and cyclophosphamide followed by BEL was safe[26]. Another phase 2, randomized, double-blind trial (ISRCTN: 47873003) showed that BEL after RTX did not increase the incidence of serious adverse events in SLE patients[27]. In this report, the 2 patients both experienced upper respiratory syndrome during follow-up, and no infusion reactions or other serious adverse reactions occurred. Eculizumab is a fully humanized IgG2/IgG4 monoclonal antibody directed at C5 that prevents the formation of the terminal complement complex. The alternative complement system can be pathogenically activated in SLE by the increased presence of immune complexes, leading to overactivation of the terminal complement complex (C5b-9) and tissue damage[28-29]. Wright RD et al. systematically reviewed the efficacy of eculizumab in 30 SLE patients with TMA in 14 clinical studies and reported that 93.3% (28/30) of these patients responded well to treatment. Eculizumab is directly recommended for complement-mediated TMA patients who have a poor response to plasma exchange and immunosuppression therapy[30]. Complex (C5b-9) tests were not performed for these two patients because of limitations. Eculizumab entered the Chinese market in November 2022; therefore, ecaluzimab was not administered to our patients. Conclusion In conclusion, early low-dose rituximab was effective for refractory SLE patients with TMA. RTX kills target cells through antibody-dependent cytotoxicity, complement-dependent cytotoxicity or direct effects, inhibits excessive cytokine release, and reduces endothelial cell damage. Patients who respond poorly to PEX and high-dose corticosteroids respond well to low-dose RTX. B-cell depletion with RTX leads to BAFF overexpression, and an increase in BAFF levels after RTX may contribute to severe flares and could limit the effectiveness of RTX in some patients with SLE. BEL can inhibit the binding of BAFF to its receptor. BEL treatment could significantly reduce the dose of glucocorticoids needed in patients with SLE with TMA. Sequential treatment with low-dose RTX and BEL could be an encouraging choice for preventing the relapse of SLE patients with TMA and rapid glucocorticoid reduction. Declarations Authors’ contributions Zhenle Yang and Suwen Liu wrote the manuscript and contributed to patient management. Zihan Zong, Qian Li and Lichun Yu contributed to patient management. Shuzhen Sun coordinated and supervised the data collection and critically reviewed the manuscript for important intellectual content. All the authors read and approved the final version of the manuscript. Funding The authors declare that no funds, grants, or other support was received during the preparation of this manuscript. Availability of data and materials The original contributions presented in the study are included in the article, and further inquiries can be directed to the corresponding author upon reasonable request. Ethics approval and consent to participate This is not applicable, as this study is a case report. Consent for publication Written informed consent for publication was obtained from the patients’ caregivers. Competing interests The authors declare that they have no competing interests. Acknowledgements We thank the parents of the two patients for providing permission to share their information. References Fanouriakis A, Tziolos N, Bertsias G, et al. Update οn the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis . 2021;80(1):14-25. doi:10.1136/annrheumdis-2020-218272. Brocklebank V, Wood KM, Kavanagh D. Thrombotic Microangiopathy and the Kidney.Clin J Am Soc Nephrol. 2018;13(2):300-317. doi:10.2215/CJN.00620117. Sun F, Wang X, Wu W, et al. TMA secondary to SLE: rituximab improves overall but not renal survival. Clin Rheumatol. 2018;37(1):213-218. doi:10.1007/s10067-017-3793-4. Chen MH, Chen MH, Chen WS, et al. Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan. Rheumatology (Oxford). 2011;50(4):768-775. doi:10.1093/rheumatology/keq311. Kwok SK, Ju JH, Cho CS,et al. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: risk factors and clinical outcome: a single centre study.Lupus. 2009;18(1):16-21. doi:10.1177/0961203308094360. Letchumanan P, Ng HJ, Lee LH, et al. A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus.Rheumatology (Oxford). 2009;48(4):399-403. doi:10.1093/rheumatology/ken510. Zhang T, Chen H, Liang S, et al. A non-invasive laboratory panel as a diagnostic and prognostic biomarker for thrombotic microangiopathy: development and application in a Chinese cohort study.PLoS One. 2014;9(11):e111992. Published 2014 Nov 5. doi:10.1371/journal.pone.0111992. Musio F, Bohen EM, Yuan CM, et al. Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus. Semin Arthritis Rheum 28:1-19. https:// doi.org/ 10. 1016/ s0049- 0172(98) 80023-1. Letchumanan P, Ng HJ, Lee LH, et al. A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus. Rheumatology (Oxford) 48:399–403. https:// doi. org/ 10. 1093/ rheum atology/ ken510. Hanai S, Kobayashi Y, Ito R, et al. Thrombotic microangiopathy with refractory lupus nephritis successfully treated by combining rituximab with belimumab. Scand J Rheumatol. 2023;52(2):227-229. doi:10.1080/03009742.2022.2140483. Alkhatib MH, Kant S, Menez S, et al. Thrombotic microangiopathy versus class IV lupus nephritis in systemic lupus erythematosus. J Nephrol. 2021;34(6):1907-1913. doi:10.1007/s40620-021-01010-4 Figueiredo CR, Escoli R, Santos P, Sofia F, Lopes K. Thrombotic microangiopathy in a patient with systemic lupus erythematosus and anti-factor H autoantibodies. CEN Case Rep. 2022;11(1):26-30. doi:10.1007/s13730-021-00627-5 Pattanashetti N, Ramachandran R, Rathi M, Nada R, Gupta KL. Plasma exchange in lupus nephritis with thrombotic microangiopathy. Nephrology (Carlton). 2019;24(8):877-878. doi:10.1111/nep.13542. Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther. 2013;15(1):R12. Published 2013 Jan 15. doi:10.1186/ar4142.[13] Stiles KP, Yuan CM, Chung EM, et al. Renal biopsy in high-risk patients with medical diseases of the kidney.Am J Kidney Dis. 2000;36(2):419-433. doi:10.1053/ajkd.2000.8998. Xing M, Yang Y, Li W. Rituximab in the treatment of systemic lupus erythematosus complicated with thrombotic microangiopathosis in 2 cases.Chinese Journal of Rheumatology, 2023,27(4):246-250,C4-2.DOI:10.3760/cma.j.cn141217-20220215-00055. Akcaü K, Batu ED,Kisaarslan AP, et al.Hematological involvement in pediatric systemic lupus erythematosus：a multi-center study[J]．Lupus，2021，30(12):1983-1990.DOI：10.1177/09612033211038824. Pons-Estel BA, Bonfa E, Soriano ER, et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR). Ann Rheum Dis. 2018;77(11):1549-1557. doi:10.1136/annrheumdis-2018-213512. Yang F, Tian J, Peng L, et al. Thrombocytopenia is an independent Risk Factor for the Prognosis of Thrombotic Microangiopathy in Chinese Patients With Systemic Lupus Erythematosus. Front Med (Lausanne). 2021;8:772607. Published 2021 Nov 8. doi:10.3389/fmed.2021.772607. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736-745. doi:10.1136/annrheumdis-2019-215089. Jones A, Muller P, Dore CJ, et al. Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial. BMJ Open. 2019;9(12):e032569. Published 2019 Dec 16. doi:10.1136/bmjopen-2019-032569. Ma W, Bai W, Wu X,et al. Successful treatment of refractory thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus with combination of plasma exchange and low-dose rituximab. Lupus. 2020;29(14):1961-1967. doi:10.1177/0961203320953473. Gualtierotti R, Borghi MO, Gerosa M, et al. Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series. Clin Exp Rheumatol. 2018;36(4):643-647. Kraaij T, Arends EJ, van Dam LS, et al. Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol Dial Transplant (2021) 36(8):1474–83. doi: 10.1093/ndt/gfaa117. Liu J, Yan M, Wen R, et al. Sequential treatment of rituximab and belimumab in thrombotic thrombocytopenia purpura associated with systemic lupus erythematous: A respective case series and literature review. Int J Rheum Dis. 2023;26(5):960-964. doi:10.1111/1756-185X.14556. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis [published correction appears in Arthritis Rheumatol. 2021 Dec;73(12):2356]. Arthritis Rheumatol. 2021;73(1):121-131. doi:10.1002/art.41466. Shipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial.Ann Intern Med. 2021;174(12):1647-1657. doi:10.7326/M21-2078. Ricklin D, Reis ES, Lambris JD. Complement in disease: a defence system turning offensive. Nat Rev Nephrol. 2016;12(7):383-401. doi:10.1038/nrneph.2016.70. Song D, Guo WY, Wang FM, et al. Complement Alternative Pathway׳s Activation in Patients With Lupus Nephritis. Am J Med Sci. 2017;353(3):247-257. doi:10.1016/j.amjms.2017.01.005. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021. Tables Tables 2 and 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table.docx Cite Share Download PDF Status: Published Journal Publication published 26 Feb, 2025 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 05 Nov, 2024 Reviews received at journal 05 Nov, 2024 Reviews received at journal 27 Oct, 2024 Reviewers agreed at journal 27 Oct, 2024 Reviews received at journal 23 Oct, 2024 Reviewers agreed at journal 19 Oct, 2024 Reviewers agreed at journal 17 Oct, 2024 Reviewers invited by journal 15 Oct, 2024 Editor invited by journal 14 Oct, 2024 Editor assigned by journal 09 Oct, 2024 Submission checks completed at journal 09 Oct, 2024 First submitted to journal 08 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5225451","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":374641380,"identity":"336af5de-1965-4665-b034-cd84e06bf507","order_by":0,"name":"Zhenle Yang","email":"","orcid":"","institution":"Shandong Provincial Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Zhenle","middleName":"","lastName":"Yang","suffix":""},{"id":374641381,"identity":"8aa42fea-1465-4933-84ba-b6bd1f63a0cd","order_by":1,"name":"Suwen Liu","email":"","orcid":"","institution":"Shandong Provincial Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Suwen","middleName":"","lastName":"Liu","suffix":""},{"id":374641382,"identity":"4e1cf2f1-703e-4d6f-8139-7788c0da260b","order_by":2,"name":"Zihan Zong","email":"","orcid":"","institution":"Shandong Provincial Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Zihan","middleName":"","lastName":"Zong","suffix":""},{"id":374641383,"identity":"7808cbcd-8f59-47f1-b919-c89611a0a1ff","order_by":3,"name":"Qian Li","email":"","orcid":"","institution":"Shandong Provincial Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Li","suffix":""},{"id":374641384,"identity":"5aeead5b-a221-4333-b583-694bce87f55b","order_by":4,"name":"Lichun Yu","email":"","orcid":"","institution":"Shandong Provincial Hospital, Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Lichun","middleName":"","lastName":"Yu","suffix":""},{"id":374641385,"identity":"94551798-51e5-4505-9633-86c13965f809","order_by":5,"name":"Shuzhen Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYDACCQYGZhDNxsx84MCHClK08LOzJR6ccYYULZL9PMaHeVuI0CE/u8f4c0HFHXuDwzwfDvA2MMjzix3Ar8XgzhkD4xlnniVuOMy74YDkDgbDmbMTCGiRyDFI5m07nGAA0mJ4hiHB4DYBLfIzcoCK/x0GOezBgcQ2IrQw3MgxbOZtOMw4s5mH4cBBYrQY3EgrZuY5djixn5nN4GDDGQnCfpGfkbz5M0/NYXs2/sOPP/+psJHnlybkMDQgQZryUTAKRsEoGAXYAQB6bEcfBiZOzQAAAABJRU5ErkJggg==","orcid":"","institution":"Shandong Provincial Hospital, Shandong University","correspondingAuthor":true,"prefix":"","firstName":"Shuzhen","middleName":"","lastName":"Sun","suffix":""}],"badges":[],"createdAt":"2024-10-08 12:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5225451/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5225451/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-025-05506-x","type":"published","date":"2025-02-26T15:58:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":77623154,"identity":"8cb74bf7-acc5-4de3-9cf0-75b239152641","added_by":"auto","created_at":"2025-03-03 16:11:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":528043,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5225451/v1/91c6cc79-5408-48e2-9f9d-e6e6c55c7cb1.pdf"},{"id":70589214,"identity":"356bc4f4-5b72-429f-954d-ee284d3288fe","added_by":"auto","created_at":"2024-12-04 16:31:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20938,"visible":true,"origin":"","legend":"","description":"","filename":"Table.docx","url":"https://assets-eu.researchsquare.com/files/rs-5225451/v1/6c445f9ea4c2df7ad1c4cd23.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sequential treatment using low-dose rituximab and belimumab for thrombotic microangiopathy with systemic lupus erythematosus","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the involvement of various organs and tissues due to the binding of self-antibodies and immune complex formation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The pathological manifestations of SLE include the deposition of immune complexes and vasculitis. Clinically, multiple organs are often affected, and the levels of specific antibodies in the serum are elevated. Thrombotic microangiopathy (TMA) syndrome is a potentially life-threatening complication and is defined as an integrated syndrome of microangiopathic haemolytic anaemia, thrombocytopenia, and organ injury[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. SLE is a major underlying cause of secondary TMA. According to reports, the incidence of SLE complicated with TMA ranges from 1\u0026ndash;4% [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], with a mortality rate as high as 33.3\u0026ndash;62.5%[\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Currently, there is no standardized treatment protocol available for the management of SLE complicated with TMA[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. We reported two patients with TMA with SLE who showed good efficacy and prognosis with sequential treatment with rituximab (RTX) and belimumab (BEL).\u003c/p\u003e \u003cp\u003ePatient 1: A 12-year-old girl presented with a 7-day history of gradually progressive bilateral lower extremity weakness, a sallow complexion and a 5-day history of fever in December 2020. The laboratory data revealed proteinuria, haematuria, pancytopenia, acute kidney injury, hypoproteinaemia, and decreased C3 and C4 levels. High titres of antinuclear antibody (ANA) and positive anti-double-stranded DNA and anti-Smith antibodies were detected. Lactic dehydrogenase (LDH) was also elevated. Lupus anticoagulant, ACL antibody, and anti-b2GP1 antibody levels and Coombs test results were all negative (Table\u0026nbsp;1). She was diagnosed with SLE. Her SLE Disease Activity Index (SLEDAI) was 24, indicating high disease activity; therefore, she was initially treated with 3 pulses of 1000 mg (20 mg/kg) intravenous methylprednisolone per day followed by intravenous methylprednisolone 48 mg per day, 20 g/day (total of 3 doses, 1 g/kg) intravenous immunoglobulin infusions and 100 mg oral hydroxychloroquine (HCQ) twice a day (3.4 mg/kg). The platelet concentration increased from 30x10\u003csup\u003e9\u003c/sup\u003e/L to 208x10\u003csup\u003e9\u003c/sup\u003e/L and then quickly decreased to 42x10\u003csup\u003e9\u003c/sup\u003e/L. Her creatinine increased from 124 \u0026micro;mol/L to 208 \u0026micro;mol/L and then decreased to 166 \u0026micro;mol/L, and her peripheral blood showed numerous schistocytes and increased lactate dehydrogenase (LDH). The patient had no history of diarrhoea, bloody stools, neuropsychiatric symptoms, or organ transplantation. Stool routine tests, coagulation function tests, pneumococcal antigen tests and magnetic resonance imaging of the brain were all negative. Based on these findings, refractory SLE and lupus nephritis with TMA were diagnosed. Despite the initial improvement, her anaemia, thrombocytopenia and renal failure recurred. PEX was performed once daily for 3 days. However, the patient\u0026rsquo;s condition failed to improve. RTX (100 mg) was administered intravenously (1 dose every 2 weeks; a total of 2 doses), along with cyclophosphamide (800 mg/m\u003csup\u003e2\u003c/sup\u003e, a total of 8 doses). After 2 doses of RTX, PLT and serum creatinine levels returned to normal. Despite follow-up laboratory examinations, which showed that her PLT and serum creatinine levels remained normalized and that her Hb gradually increased to normal levels, the patient still had proteinuria. Therefore, intravenous BEL (10 mg/kg) and oral mycophenolate mofetil (MMF, 1 g/day) were prescribed. She was maintained on BEL, MMF (1 g per day) and HCQ (0.2 g per day), and her prednisolone treatment was stopped in April 2023, with an SLEDAI score of 0. She developed upper respiratory syndrome twice during the follow-up, and these conditions were cured by symptomatic treatment. At the last visit, the patient was maintained with BEL, HCQ and MMF and had no relapse.\u003c/p\u003e \u003cp\u003ePatient 2: A 12-year-old girl with a 1-week history of fever, a 5-day history of polyarthritis and a 4-day history of haematuria and oedema was admitted to our centre in December 2021. Routine blood tests revealed thrombocytopaenia, anaemia and an elevated reticulocyte count. Urine tests revealed albuminuria and haematuria, with an elevated 24-hour urine protein level (24hUPro). Peripheral blood and bone marrow smears showed numerous schistocytes. ANA and anti-double-stranded DNA were positive, and decreased C3 and C4 levels were observed. Lupus anticoagulant, ACL antibodies, anti-b2GP1 antibodies and Coombs tests were all negative (Table\u0026nbsp;1). The patient had no history of diarrhoea, bloody stools, neuropsychiatric symptoms, or organ transplantation. Stool routine tests, coagulation function tests, pneumococcal antigen tests and magnetic resonance imaging of the brain were all normal. She was treated with intravenous methylprednisolone 48 mg per day. Oral HCQ (100 mg) was prescribed twice per day. The PLT initially improved from 80 x10\u003csup\u003e9\u003c/sup\u003e/L to 122x10\u003csup\u003e9\u003c/sup\u003e/L. Renal biopsy was performed to evaluate her renal dysfunction. We detected IgA(++), IgG(+++), C3(+++), Fib(+), IgM(+), and C1q(+++) using immunofluorescence. Under light microscopy, a total of 13 glomeruli were observed, and the findings were as follows: moderate-severe diffuse proliferation of the mesangial matrix, diffuse endocapillary hypercellularity composed of swollen endothelial cells, leukocytes, irregularly thickened glomerular capillary wall segments, double track changes, capillary lumen stenosis, and scattered thrombosis. ADAMTS13 inhibitor and antifactor H autoantibodies were negative. The patient also underwent whole-exon gene sequencing, which revealed that the proband had heterozygous mutations in DNASE1 (c.653T\u0026thinsp;\u0026gt;\u0026thinsp;A, p.I218N, Chr16:3707291). We did not find any gene markers related to TMA recurrence. SLE with TMA was diagnosed, and haematological recovery was observed after she was treated with 2 pulses of 500 mg methylprednisolone (10 mg/kg) per day for 3 days followed by 60 mg/day oral prednisolone (1 mg/kg). Despite the initial improvement, thrombocytopenia, anaemia, and increased LDH and serum creatinine levels recurred. Treatment with high-dose corticosteroids was interrupted because of CMV infection. Intravenous immunoglobulin infusions of 20 g/day (total of 3 doses, 1 g/kg) along with PEX were performed once daily for 5 days and then every two days 5 times. However, the patient\u0026rsquo;s condition failed to improve. A total of 100 mg RTX per 2 weeks with 800 mg cyclophosphamide (500 mg/m\u003csup\u003e2\u003c/sup\u003e) was administered to this patient when the CMV infection was cured. PLT and serum creatinine levels returned to normal after 3 doses of RTX and 1 dose of cyclophosphamide. Treatment with cyclophosphamide was interrupted because of a gastrointestinal reaction. Intravenous BEL (10 mg/kg) and oral MMF (1 g/day) were administered because of persistent gross haematuria and moderate levels of proteinuria. She developed upper respiratory syndrome once during the follow-up, which was resolved by symptomatic treatment. At the last visit, the patient had been maintained with BEL, HCQ and MMF.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;1\u0026emsp;Clinical and laboratory baseline data of the 2 patients\u003c/p\u003e\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"555\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eItem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003ePatient 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003ePatient 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference range\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eRace/Ethnicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eYellow race/The Han nationality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eYellow race/The Han nationality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAge/Gender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e12/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e12/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eBody surface are (m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eOral ulcers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eNonscarring alopecia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eArthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eSerositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eNeurologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eESR (mm/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eCRP (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eWhite blood cells (x 109/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003e3.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e4-10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eHaemoglobin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e115-150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003ePlatelets (x 10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e100-300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eReticulocyte proportion (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0.5-2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eTBil (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e12.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e3.5-23.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eDBil (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0.5-6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eALT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e7-40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAST (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e13-35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAlbumin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e23.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e40-55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eSerum creatinine (umol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e40-105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eLactate dehydrogenase (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e633.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e516\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e120-250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e24hUPro (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e4.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e9.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e＜0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eUrine erythrocytes (/HPF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1769.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eD-Dimer (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e2.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003ePT (seconds)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e7.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e9.2-12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAPTT (seconds)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e23.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e29.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e25.1-36.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eFibrinogen (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e2.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e2.0-4.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eANA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1:1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1:1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e＜1:100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAnti-dsDNA antibody (IU/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e204.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e302.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAnti-Smith antibody (IU/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAnti-SSA antibody (IU/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAnti-SSB antibody (IU/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e8.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0.92-1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eACL antibodies (CU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e2,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eAnti-b2GPI antibodies IgG (CU)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0-20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eC3 (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0.79\u0026ndash;1.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eC4 (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e0.1\u0026ndash;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eBlood smear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eSchistocytes and\u003cbr\u003e\u0026nbsp;reduced platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eSchistocytes and\u003cbr\u003e\u0026nbsp;reduced platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003eBone marrow biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eSchistocytes and\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003eSchistocytes and\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003ereduced platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003ereduced platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cp\u003eAbbreviations: ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; TBil, total bilirubin; DBil, direct bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 24hUPro, 24-h urine protein; PT, prothrombin time; APTT, activated partial thromboplastin time; ANA, anti-nuclear antibody; Anti-SSA, anti-Sj\u0026ouml;gren\u0026apos;s syndrome A; Anti-SSB, anti-Sj\u0026ouml;gren\u0026apos;s syndrome B; LA, lupus anticoagulant; ACL, anticardiolipin; Anti-b2GP1, anti-\u0026beta;2-glycoprotoein 1; C3, complement 3; C4, complement 4; IgG, immunoglobin G.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTMA is less common but is a potentially lethal disease affecting small vessels. Classically, TMA presents with a triad of haemolytic anaemia, thrombocytopaenia, and ischaemic end-organ failure (most commonly, the kidneys). More commonly, TMA manifests as a secondary complication of other systemic diseases, often autoimmune diseases, including SLE [2.11]. The differential diagnosis of TMA in patients with SLE includes antiphospholipid antibody syndrome, thrombocytopenic purpura, complement-mediated and infection-associated haemolytic uraemic syndrome, drug-mediated TMA, and malignant hypertension [12]. Previous studies have reported that TMA is an independent risk factor for poor renal outcomes in patients with lupus nephritis, and patients with this condition may have an inadequate response to conventional therapy compared to those with lupus nephritis but without TMA, leading to a higher mortality rate [10.13-14]. Clinically, it can be challenging to differentiate TMA from fever, thrombocytopenia, and renal function impairment caused by lupus activity itself, which can complicate diagnosis and treatment decisions. Kidney biopsy can\u0026nbsp;confirm renal microangiopathy[15]. However, when a kidney biopsy cannot be performed due to special circumstances, TMA can be indicated by specific laboratory indicators, such as a decrease in haemoglobin levels, a decreased platelet count, elevated LDH levels, the presence of fragmented red blood cells in the peripheral blood, and a negative Coombs test [16]. The laboratory examination of our 2 patients revealed a decrease in haemoglobin levels; a decrease in platelet count; an increase in LDH levels; the presence of fragmented red blood cells in the peripheral blood; and decreases in the Coombs test,\u0026nbsp;ACL antibodies, and anti-b2GP1 antibodies; and decreased C3 and C4 levels.\u0026nbsp;ADAMTS13 inhibitor and anti‑factor H autoantibodies were negative\u0026nbsp;in Patient 2, and a\u0026nbsp;renal biopsy was\u0026nbsp;also\u0026nbsp;performed\u0026nbsp;in Patient 2,\u0026nbsp;revealing histological findings of wire-loop lesions with double contours and the formation of microthrombi in glomerular capillaries. However, in Patient 1, kidney biopsy could not be performed initially due to the severity of the disease and the progressive decrease in PLT levels.\u0026nbsp;Special medication, infection, organ transplantation and other medical history were excluded for the two patients presented in this study.\u003c/p\u003e\n\u003cp\u003eTreatment for SLE with TMA includes high-dose corticosteroids, PEX, intravenous immunoglobulin infusions and immunosuppression therapy.\u003c/p\u003e\n\u003cp\u003eRenal replacement therapy is needed for patients with progressive deterioration of kidney function or severe renal insufficiency[17-18]. Immunosuppression therapy for SLE patients with TMA includes corticosteroids, cyclophosphamide, and MMF [19]. The present study reported 2 patients who received high-dose corticosteroids, intravenous immunoglobulin infusions, and PEX at the initial stage. Both patients had recurrent thrombocytopenia, anaemia and increased serum creatinine levels. RTX is a human-murine chimeric anti-CD20 antibody that cankill target cells through antibody-dependent cytotoxicity, complement-dependent cytotoxicity or direct effects, inhibit excessive cytokine release, and reduce endothelial cell damage. The European League Against Rheumatism stated that RTX should be considered for treating organ-threatening, refractory lupus[20-21], and no guidelines for the treatment of TMA in patients with LN have been established. It has been reported that RTX is a standard treatment for relapsed and refractory TMA based on the excellent outcomes observed in patients who respond poorly to PEX and high-dose corticosteroids[22]. The optimal dose and schedule of RTX for TMA are unclear, but the most common approach is 375 mg/m\u003csup\u003e2\u003c/sup\u003e RTX once or twice per week for 4 to 8 weeks. The satisfactory efficacy of reduced-dose regimens of 100 mg weekly for 4 weeks has been demonstrated in a previous study[22]. In our report, Patient 1 was prescribed low-dose RTX (100 mg weekly for 2 weeks), and Patient 2 was prescribed low-dose RTX (100 mg weekly for 3 weeks). We chose this dose in consideration of the high cost and infection risk of RTX. Both patients responded well to low-dose RTX.\u003c/p\u003e\n\u003cp\u003eBEL is a recombinant human IgG-1λ monoclonal antibody that inhibits the binding of B-cell activating factor (BAFF) to its receptor. Some studies have revealed that B-cell depletion with RTX leads BAFF overexpression[23]. An increase in BAFF levels after RTX may contribute to severe flares and could limit the effectiveness of RTX in some patients with SLE [21]. This finding provides a basis for the use of RTX sequentially with BEL therapy in SLE patients. The phase II SynBioSe study showed significant clinical and immunological improvements from baseline in patients with severe refractory SLE who received RTX followed by BEL and that patients maintained a response over two years [24]. The 2019 update of the EULAR recommendations for the management of SLE suggested that BEL is beneficial for tapering daily doses of glucocorticoids to acceptable levels (a maximum of 7.5 mg/d)[20]. S Hanai et al reported the case of a young girl who was diagnosed with TMA with refractory LN and who received\u0026nbsp;RTX\u0026nbsp;combined with\u0026nbsp;BEL, which gradually improved the patient’s LN and TMA. Prednisone was tapered to 5 mg/day, and the patient experienced no recurrence for approximately 3 years [10]. Jun Liu et al reported that patients who were all diagnosed with thrombotic thrombocytopenia purpura with SLE received sequential treatment with\u0026nbsp;RTX\u0026nbsp;and\u0026nbsp;BEL. All 4 patients recovered with an SLE Disease Activity Index score of 0 and reached the prednisolone dose goal of \u0026lt;7.5 mg/d without relapse[24]. We reported sequential therapy of BEL followed by RTX in patients with SLE with TMA who had good follow-up outcomes and no glucocorticoid doses.\u003c/p\u003e\n\u003cp\u003eThe most common adverse reaction to RTX is an infusion reaction, and the most common adverse reaction to BEL is infection. In a randomized controlled trial (NCT02260934), researchers showed that a combination of RTX and cyclophosphamide followed by BEL was safe[26]. Another phase 2, randomized, double-blind trial (ISRCTN: 47873003) showed that BEL after RTX did not increase the incidence of serious adverse events in SLE patients[27]. In this report, the 2 patients both experienced upper respiratory syndrome during follow-up, and no infusion reactions or other serious adverse reactions occurred.\u003c/p\u003e\n\u003cp\u003eEculizumab is a fully humanized IgG2/IgG4 monoclonal antibody directed at C5 that prevents the formation of the terminal complement complex. The alternative complement system can be pathogenically activated in SLE by the increased presence of immune complexes, leading to overactivation of the terminal complement complex (C5b-9) and tissue damage[28-29]. Wright RD et al. systematically reviewed the efficacy of eculizumab in 30 SLE patients with TMA in 14 clinical studies and reported that 93.3% (28/30) of these patients responded well to treatment. Eculizumab is directly recommended for complement-mediated TMA patients who have a poor response to plasma exchange and immunosuppression therapy[30]. Complex (C5b-9) tests were not performed for these two patients because of limitations. Eculizumab entered the Chinese market in November 2022; therefore, ecaluzimab was not administered to our patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, early low-dose rituximab was effective for refractory SLE patients with TMA. RTX kills target cells through antibody-dependent cytotoxicity, complement-dependent cytotoxicity or direct effects, inhibits excessive cytokine release, and reduces endothelial cell damage. Patients who respond poorly to PEX and high-dose corticosteroids respond well to low-dose RTX. B-cell depletion with RTX leads to BAFF overexpression, and an increase in BAFF levels after RTX may contribute to severe flares and could limit the effectiveness of RTX in some patients with SLE. BEL can inhibit the binding of BAFF to its receptor. BEL treatment could significantly reduce the dose of glucocorticoids needed in patients with SLE with TMA. Sequential treatment with low-dose RTX and BEL could be an encouraging choice for preventing the relapse of SLE patients with TMA and rapid glucocorticoid reduction.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhenle Yang and Suwen Liu wrote the manuscript and contributed to patient management. Zihan Zong, Qian Li and Lichun Yu contributed to patient management. Shuzhen Sun coordinated and supervised the data collection and critically reviewed the manuscript for important intellectual content. All the authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support was received during\u003c/p\u003e\n\u003cp\u003ethe preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article, and further inquiries can be directed to the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is not applicable, as this study is a case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication was obtained from the patients\u0026rsquo; caregivers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the parents of the two patients for providing permission to share their information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFanouriakis A, Tziolos N, Bertsias G, et al. Update \u0026omicron;n the diagnosis and management of systemic lupus erythematosus. \u003cem\u003eAnn Rheum Dis\u003c/em\u003e. 2021;80(1):14-25. doi:10.1136/annrheumdis-2020-218272.\u003c/li\u003e\n\u003cli\u003eBrocklebank V, Wood KM, Kavanagh D. Thrombotic Microangiopathy and the Kidney.Clin J Am Soc Nephrol. 2018;13(2):300-317. doi:10.2215/CJN.00620117.\u003c/li\u003e\n\u003cli\u003eSun F, Wang X, Wu W, et al. TMA secondary to SLE: rituximab improves overall but not renal survival. Clin Rheumatol. 2018;37(1):213-218. doi:10.1007/s10067-017-3793-4.\u003c/li\u003e\n\u003cli\u003eChen MH, Chen MH, Chen WS, et al. Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan. Rheumatology (Oxford). 2011;50(4):768-775. doi:10.1093/rheumatology/keq311.\u003c/li\u003e\n\u003cli\u003eKwok SK, Ju JH, Cho CS,et al. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: risk factors and clinical outcome: a single centre study.Lupus. 2009;18(1):16-21. doi:10.1177/0961203308094360.\u003c/li\u003e\n\u003cli\u003eLetchumanan P, Ng HJ, Lee LH, et al. A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus.Rheumatology (Oxford). 2009;48(4):399-403. doi:10.1093/rheumatology/ken510.\u003c/li\u003e\n\u003cli\u003eZhang T, Chen H, Liang S, et al. A non-invasive laboratory panel as a diagnostic and prognostic biomarker for thrombotic microangiopathy: development and application in a Chinese cohort study.PLoS One. 2014;9(11):e111992. Published 2014 Nov 5. doi:10.1371/journal.pone.0111992.\u003c/li\u003e\n\u003cli\u003eMusio F, Bohen EM, Yuan CM, et al. Review of thrombotic thrombocytopenic purpura in the setting of systemic lupus erythematosus. Semin Arthritis Rheum 28:1-19. https:// doi.org/ 10. 1016/ s0049- 0172(98) 80023-1.\u003c/li\u003e\n\u003cli\u003eLetchumanan P, Ng HJ, Lee LH, et al. A comparison of thrombotic thrombocytopenic purpura in an inception cohort of patients with and without systemic lupus erythematosus. Rheumatology (Oxford) 48:399\u0026ndash;403. https:// doi. org/ 10. 1093/ rheum atology/ ken510.\u003c/li\u003e\n\u003cli\u003eHanai S, Kobayashi Y, Ito R, et al. Thrombotic microangiopathy with refractory lupus nephritis successfully treated by combining rituximab with belimumab. Scand J Rheumatol. 2023;52(2):227-229. doi:10.1080/03009742.2022.2140483.\u003c/li\u003e\n\u003cli\u003eAlkhatib MH, Kant S, Menez S, et al. Thrombotic microangiopathy versus class IV lupus nephritis in systemic lupus erythematosus. J Nephrol. 2021;34(6):1907-1913. doi:10.1007/s40620-021-01010-4\u003c/li\u003e\n\u003cli\u003eFigueiredo CR, Escoli R, Santos P, Sofia F, Lopes K. Thrombotic microangiopathy in a patient with systemic lupus erythematosus and anti-factor H autoantibodies. CEN Case Rep. 2022;11(1):26-30. doi:10.1007/s13730-021-00627-5\u003c/li\u003e\n\u003cli\u003ePattanashetti N, Ramachandran R, Rathi M, Nada R, Gupta KL. Plasma exchange in lupus nephritis with thrombotic microangiopathy. Nephrology (Carlton). 2019;24(8):877-878. doi:10.1111/nep.13542.\u003c/li\u003e\n\u003cli\u003eSong D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther. 2013;15(1):R12. Published 2013 Jan 15. doi:10.1186/ar4142.[13]\u003c/li\u003e\n\u003cli\u003eStiles KP, Yuan CM, Chung EM, et al. Renal biopsy in high-risk patients with medical diseases of the kidney.Am J Kidney Dis. 2000;36(2):419-433. doi:10.1053/ajkd.2000.8998.\u003c/li\u003e\n\u003cli\u003eXing M, Yang Y, Li W. Rituximab in the treatment of systemic lupus erythematosus complicated with thrombotic microangiopathosis in 2 cases.Chinese Journal of Rheumatology, 2023,27(4):246-250,C4-2.DOI:10.3760/cma.j.cn141217-20220215-00055.\u003c/li\u003e\n\u003cli\u003eAkca\u0026uuml; K, Batu ED,Kisaarslan AP, et al.Hematological involvement in pediatric systemic lupus erythematosus：a multi-center study[J]．Lupus，2021，30(12):1983-1990.DOI：10.1177/09612033211038824.\u003c/li\u003e\n\u003cli\u003ePons-Estel BA, Bonfa E, Soriano ER, et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR). Ann Rheum Dis. 2018;77(11):1549-1557. doi:10.1136/annrheumdis-2018-213512.\u003c/li\u003e\n\u003cli\u003eYang F, Tian J, Peng L, et al. Thrombocytopenia is an independent Risk Factor for the Prognosis of Thrombotic Microangiopathy in Chinese Patients With Systemic Lupus Erythematosus. Front Med (Lausanne). 2021;8:772607. Published 2021 Nov 8. doi:10.3389/fmed.2021.772607.\u003c/li\u003e\n\u003cli\u003eFanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736-745. doi:10.1136/annrheumdis-2019-215089.\u003c/li\u003e\n\u003cli\u003eJones A, Muller P, Dore CJ, et al. Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial. BMJ Open. 2019;9(12):e032569. Published 2019 Dec 16. doi:10.1136/bmjopen-2019-032569.\u003c/li\u003e\n\u003cli\u003eMa W, Bai W, Wu X,et al. Successful treatment of refractory thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus with combination of plasma exchange and low-dose rituximab. Lupus. 2020;29(14):1961-1967. doi:10.1177/0961203320953473.\u003c/li\u003e\n\u003cli\u003eGualtierotti R, Borghi MO, Gerosa M, et al. Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series. Clin Exp Rheumatol. 2018;36(4):643-647.\u003c/li\u003e\n\u003cli\u003eKraaij T, Arends EJ, van Dam LS, et al. Long-term effects of combined B-cell immunomodulation with rituximab and belimumab in severe, refractory systemic lupus erythematosus: 2-year results. Nephrol Dial Transplant (2021) 36(8):1474\u0026ndash;83. doi: 10.1093/ndt/gfaa117.\u003c/li\u003e\n\u003cli\u003eLiu J, Yan M, Wen R, et al. Sequential treatment of rituximab and belimumab in thrombotic thrombocytopenia purpura associated with systemic lupus erythematous: A respective case series and literature review. Int J Rheum Dis. 2023;26(5):960-964. doi:10.1111/1756-185X.14556.\u003c/li\u003e\n\u003cli\u003eAtisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis [published correction appears in Arthritis Rheumatol. 2021 Dec;73(12):2356]. Arthritis Rheumatol. 2021;73(1):121-131. doi:10.1002/art.41466.\u003c/li\u003e\n\u003cli\u003eShipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial.Ann Intern Med. 2021;174(12):1647-1657. doi:10.7326/M21-2078.\u003c/li\u003e\n\u003cli\u003eRicklin D, Reis ES, Lambris JD. Complement in disease: a defence system turning offensive. Nat Rev Nephrol. 2016;12(7):383-401. doi:10.1038/nrneph.2016.70.\u003c/li\u003e\n\u003cli\u003eSong D, Guo WY, Wang FM, et al. Complement Alternative Pathway׳s Activation in Patients With Lupus Nephritis. Am J Med Sci. 2017;353(3):247-257. doi:10.1016/j.amjms.2017.01.005.\u003c/li\u003e\n\u003cli\u003eKidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 2 and 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Thrombotic microangiopathy, systemic lupus erythematosus, rituximab, belimumab","lastPublishedDoi":"10.21203/rs.3.rs-5225451/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5225451/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eThrombotic microangiopathy (TMA) is a serious complication that can occur in patients with systemic lupus erythematosus (SLE), and TMA adversely affects prognosis and increases mortality. The treatment of TMA often requires immunosuppressive agents, high-dose corticosteroids and plasma exchange (PEX). Both rituximab (RTX) and belimumab (BEL) target B cells. The combination of RTX and BEL has recently been used for refractory and severe organ involvement in systemic lupus erythematosus. However, the clinical outcome of patients with TMA and SLE treated with sequential therapy between RTX and BEL remains elusive.\u003c/p\u003e\u003ch2\u003eCase Series:\u003c/h2\u003e \u003cp\u003eWe reported 2 patients who were diagnosed with SLE with TMA and were administered a combination treatment of high-dose corticosteroids, immunoglobulin, and PEX at the initial stage. No improvements in microangiopathic anaemia, thrombocytopenia, or renal failure were observed. Low-dose RTX was administered in both patients, and both patients responded well. BEL was utilized to rapidly reduce the reliance on these agents and prevent the relapse of SLE at the maintenance stage. Ultimately, 2 patients fully recovered with an SLE Disease Activity Index score of 0, and prednisolone was stopped without relapse.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSequential treatment with low-dose RTX and BEL could be an encouraging approach for the treatment of TMA in patients with SLE and rapid glucocorticoid reduction.\u003c/p\u003e","manuscriptTitle":"Sequential treatment using low-dose rituximab and belimumab for thrombotic microangiopathy with systemic lupus erythematosus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-04 16:30:55","doi":"10.21203/rs.3.rs-5225451/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-06T04:42:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-05T06:40:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-27T19:21:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"159247561018790977587279430943245107550","date":"2024-10-27T18:49:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-24T02:27:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"145756726476066518383226931163561045080","date":"2024-10-19T07:36:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35312852992841354611371712299574610763","date":"2024-10-17T09:45:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-15T12:56:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-14T12:17:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-09T11:14:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-09T11:13:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2024-10-08T12:37:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8bf0b974-05c0-4600-9866-9757e47b37a0","owner":[],"postedDate":"December 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-03T16:08:12+00:00","versionOfRecord":{"articleIdentity":"rs-5225451","link":"https://doi.org/10.1186/s12887-025-05506-x","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2025-02-26 15:58:02","publishedOnDateReadable":"February 26th, 2025"},"versionCreatedAt":"2024-12-04 16:30:55","video":"","vorDoi":"10.1186/s12887-025-05506-x","vorDoiUrl":"https://doi.org/10.1186/s12887-025-05506-x","workflowStages":[]},"version":"v1","identity":"rs-5225451","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5225451","identity":"rs-5225451","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}