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1 MINISTRY OF EDUCATION AND TRAINING MINISTRY OF MILITARY MILITARY MEDICAL UNIVERSITY BUI VAN KHANH STUDY ON THE IMMUNE MODIFICATION AND EFFECTIVENESS OF TREATMENT IN PATIENTS WITH LUPUS NEPHRITIS AFTER INDUCTION TREATMENT WITH MYCOPHENOLATE MOFETIL Major: BIO-MEDICAL SCIENCE Code: 9720101 SUMMARY OF DISSERTATION MEDICAL DOCTOR HA NOI - 2020 The work has been completed at: MILITARY MEDICAL UNIVERSITY Supervisors: Assoc Prof NGUYEN DANG DUNG Assoc Prof NGUYEN VAN ĐOAN Reviewer 1: Reviewer 2: Reviewer 3: The dissertation is presented at the Academic -level Dissertation Assessment Council at Military Medical University Time:… date …month… 2020 The dissertation can be found at: The library of National Academy of Public The library of Military Medical University The library of Bach Mai Hospital PREFACE The necessary of study Systemic lupus erythematosus is the first autoimmune disease was described, which characterized by heterogeneous, multisystem involvement and the production of an array of autoantibodies There is no gold standard test for the diagnosis of SLE The first classification criteria for SLE were developed by the Ameriacan Rheumatism Association in 1971 The revised criteria for the classification of SLE were published in 1982 and last time in 1997 In 2012 the Systemic International Collaborating Clinics group to further revise the ACR classification criteria SLE can affect almost any organ and display a broad spectrum of manifestations Renal involvement in SLE remains the strongest predictor of overall patient morbidity and mortality.The presence of autoantibodies against a variety of ubiquitous self-antigens is a hallmark of systemic lupus erythematosus Mechanism of autoantibody production would require a thorough inderstanding of the loss of self-tolerance in both T and B cells Management of lupus nephritis has always been of interest to studys around the world and there have been numerous randomized clinical trials that classify and evaluate the role of immunosuppressant drugs in the treatment of lupus nephritis Mycophenolate mofetil (MMF) is a new immunosuppressant, has the ability to inhibit differentiation of both T and B Lymphocytes There are numerous randomized clinical trials assessing the role of MMF in the treatment of lupus nephritis Recently guideline for lupus nephrits worldwide as well as in Vietnam, have agreed to the indication of MMF for the treatment of lupus nephritis In Vietnam currently no study to assess the effectiveness and immune modification of MMF in treating lupus nephritis Therefore, we conducted the dissertation “Study on the immune modification and effectiveness of treatment in patients with lupus nephritis after induction treatment with Mycophenolate mofetil” for purposes: Investigation of clinical changes, paraclinincal and some immune modifications in patients with lupus nephritis after induction therapy was indicated Mycophenolate mofetil Assess the effectiveness of Mycophenolate mofetil in induction therapy in patients with lupus nephritis and the relationship with immune modifications Summary of new main scientific contribution of the dissertation • The first study to evaluate the effectiveness of treatment and immune modification in adult patients with lupus nephritis, who were treated with the protocol have MMF The results of this study can be used to compare with national and international studies • The first study at the Allergy Center - MDLS Bach Mai Hospital performed the kidney biopsy to select patients indicate to MMF treatment according to histopathological results of kidney biopsy This study is a prelude to the decision on kidney biopsy in patients with lupus nephritis and become the routine at the Center before deciding on treatment • The results of study show that the patients with lupus nephritis receiving the protocol have MMF has a high response to treatment The study provides additional information for clinicians who have additional treatment options for patients with lupus nephritis, especially among patients of childbearing age due to limitations of CYC therapy There is a high risk of ovarian failure and a sequela unable to have children in the future Construct of dissertation The dissertation includes 150 pages in which: preface pages, overview of study 44 pages, subject and method of study 16 pages, results of study 36 pages, discussion 49 pages, conclusion pages, and limitations of study page The dissertation includes 63 tables, pictures 15 charts List of reference include 142 (25 Vietnamese,117 English) Chapter 1: OVERVIEW OF STUDY The diagnosis of SLE and lupus neprhtis 1.1 The diagnosis of SLE SLE is a heterogeneous autoimmune disease that damages many organ systems Until now did not have hallmark for diagnose of SLE, so diagnosis was based on the many of criteria Because of this, classification criteria for SLE were developed by the Ameriacan Rheumatism Association in 1971 and revised in 1982 and 1997 to fix some limitations of old classification The Systemic International Collaborating Clinics group to further revise the ACR classification criteria with 11 clinical criterias and immune criterias Definition of diagnosis SLE base on ACR 1997 The patients were diagnosed SLE if they have any or more of the 11 criteria are present When tested this SLE criteria in patient population, sensitivity and specificity to the SLE patients was 96% Definition of diagnosis SLE base on SLICC- 2012 The patients were diagnosed SLE if they have any or more of the 17 criteria are present but at least clinical criteria and immune criteria or have evidence of lupus nephritis in biopsy with positive to ANA or dsDNA 1.2 Definition of lupus nephritis Patient with lupus nephritis were diagnosed by ACR • Patient were diagnosed SLE by ACR 1997 • Patient have persistent proteinuria > 0,5g per day or greater than 3+ by dipstick, and/or cellular casts including red cell, hemoglobin, granular, tubular or mixed • Patient were renal biopsy demonstrating immune complex-mediated glomerulonephritis compatible lupus nephritis Pathogenesis of lupus nephritis Renal disease ranks as the foremost cause of morbidity and mortality in systemic lupus erythematosus Yet, the pathogenesis of lupus nephritis has not been fully elucidated Numerous mediators and mechanisms have been suggested as drivers of the disease These include dysregulation of the innate immune system, pro-inflammatory cytokine overproduction, impaired B- and T-cell tolerance/regulation, as well as increased expression of various chemokines and other regulators Experiments, mostly based on lupus-prone mouse models, suggest that the steps and events leading to the development of SLE can be parsed into two phases: systemic autoimmunity and target organ injury The systemic autoimmune response: SLE is characterized by the activation of self-reactive B cells and T cells, largely directed to nuclear antigens The consequence of this lymphocyte activation is the elaboration of anti-DNA autoantibodies, one of the hallmarks of this disease In addition to activation of the adaptive arm of the immune system, cells in the innate arm of the immune system, including dendritic cells and macrophages, are also activated in this disease The phage target organ inury: Although several different end organs can be targeted in SLE, the pathogenic events leading to disease are fairly similar, involving both infiltrating leukocytes as well as resident nonimmune cells Briefly, the deposition of autoantibodies and immune complexes in the kidneys can initiate tissue injury, followed by recruitment of inflammatory leukocytes into the kidneys Cytokines, chemokines, and various mediators released by the infiltrating leukocytes as well as resident renal cells can lead to a vicious cycle of inflammation, leading to acute, then chronic tissue injury 2.1 The role of auto-antibodies The role of antinuclear antibodies –ANA and nucleosome in lupus nephritis The presence of autoantibodies directed against several nuclear and cytoplasmic antigens is a hallmark of SLE The nucleosome is the fundamental packing unit of DNA, playing a key role in controlling the expression of genetic information by regulating access to certain proteins It is believed to be a major autoantigen in SLE Hence, nucleosome and antinucleosome antibodies can contribute to the pathogenesis of lupus nephritis in a wide variety of ways The role of anti-DNA antibodies and immune complexes in lupus nephritis The first-time role of anti-dsDNA in SLE was described in 1957 and then in lupus nephritis Anti-DNA antibodies emerge as a key diagnostic and prognostic marker, being actively involved in the pathogenesis of lupus nephritis owing to their ability to bind to cell surface antigens or components of the glomerular matrix either directly (cross-reactivity) or indirectly (via chromatin-containing bridges) Three mechanisms have been proposed to explain the ability of anti-dsDNA antibodies to localize to the kidney The first mechanism is based on the formation of immune complexes, where anti-DNA antibodies form complexes with DNA/nucleosomes released from apoptotic cells, and these immune complexes can deposit in the kidney and drive downstream inflammatory cascades The second mechanism, referred to as the planted antigen hypothesis, suggests that anti-DNA antibodies can directly target the kidney by reacting with DNA/nucleosomes trapped in the glomerular matrix The trapping of DNA/nucleosomes in the glomerular matrix and the GBM has been attributed to interactions between the positively charged histone DNA and negatively charged glomerular matrix The third mechanism relies on the cross-reactivity between intrinsic non-DNA glomerular antigens and anti-DNA antibodies Laminin, heparan sulfate, as well as collagen type IVof GBM, alpha-actinin and ribosomal P protein of mesangial cells, and ribosomal P protein of endothelial cells, are all potential non-DNA autoantigens that can be recognized by anti-DNA antibodies in intrinsic kidney cells 2.2 The role of complemt system The complement system is a humoral component of the natural immune system that contains about 30 proteins, which exist in two forms that circulate in the blood and form adhesions on cell membranes Although activation of the complementary system causes damage to tissues and organs, studies in mice and later on SLE patients suggest that deficiencies of complement components follow the classical pathway such as C1q, C1r, C2 and C4 easily lead to SLE C1q resistance is both specific and sensitive in SLE In invitro studies it has been shown that resistance to C1q acts as a coupling for the combination of autoantibodies with complement and complement complexes, leading to increased lupus nephritis lesions C1q resistance is strongly associated with lupus kidney damage due to glomerular deposition 2.3 The role of immune cells The role of Lymphocyte T: T cells also play a key role in the pathogenesis of lupus nephritis The role that T cells play in driving the systemic autoimmunity in lupus-cell lymphocytes are more common than B-lymphocytes when lymphocytic infiltrates are detected on renal biopsy specimens, including TCD4 + and TCD8 + lymphocytes Research on these cells has been difficult due to limited kidney biopsy samples Several studies show that TCD4 + lymphocytes in lupus nephritis are inclined to the Th1 phenotype, especially in patients with proliferative nephritis, but these findings have not been widely accepted The role of Lymphocyte B: Both B and plasma cells are found in the kidneys of patients with lupus nephritis Research in mice shows that inflamed tissue becomes the home of plasma cells Analysis of the Ig receptors of B lymphocytes isolated from the kidney tissue biopsy piece of lupus patients showed evidence of monoclonal development, indicating that the immune response occurs locally, these findings Together with evidence of monoclonal T lymphocyte development, further support the hypothesis that the renal antigen that controls the local immune response may amplify kidney tissue damage The role of Macrophages: Macrophages are key cellular determinants of pathogenesis and progression in lupus nephritis Their recruitment has been documented in both lupus-prone mice and lupus nephritis patients Recruited macrophages are located in both the glomerular tuft and tubulointerstitium and constitute the major cell type in glomerular crescents Importantly, renal infiltrating macrophages are mainly activated type II macrophages Macrophages can product a lot of cytokine such as interleukin- 1, -6, -12, -23 and pro-inflammation like iNOS, ROS Characteristic of histapathological of lupus nephritis Renal biopsy plays an important role in the diagnosis and treatment of patients with lupus kidney damage, most of the components of the kidney are damaged in lupus such as glomeruli, kidney tubules, and kidney vessels Lupus nephritis has complex clinical manifestations as well as histopathological lesions that vary greatly from patient to patient and stage of the disease Because of this, the WHO has proposed and introduced a classification of lupus kidney damage based on histopathological histology of kidney biopsy in 1982 and updated in 1995, this standard is now adopted by the International Nephrology Association/ Association of Diseases The International Society of Nephrology / Renal Pathology Society (ISN/ RPS) was updated in May 2003 and classification of renal damage into six different groups Treatment of SLE and lupus nephritis 4.1 The treatment of SLE SLE is a complex pathology, damage of many organ systems, and at different times, lesions of varying degrees, with varying degrees of severity Therefore, there is no uniform formula for the treatment of a patient The European Union Against Rheumatism (EULAR), for the first time, made a recommendation for treatment of SLE in 2008 and was updated in 2019 Following this guide, SLE patients are treated based on disease activity level and target organ damage Treatment drugs include: Glucocorticoid-(GC), Hydroxycloroquine (HCQ), Methotrexate (MTX), Cyclosporine A (CsA), Cycophosphamide (CYC), Azathioprine (AZA), MMF, biologics 4.2 The treatment of lupus nephritis The ultimate goal of treating lupus nephritis is to improve the quality of life of the patient as well as to improve the patient's survival After decades of multi-center clinical trial studies have been conducted with various drugs to find the best treatment strategy for patients Treatment of lupus nephritis is based on different severity, with or without histopathological classification, and is divided into two stages of induction and maintenance treatment 4.2.1.Induction therapy for lupus nephritiss Protocol of therapy for lupus nephritis by Vietnam Ministry of Health published 2015 • Protocol for patients with renal biopsy: Patients with class I and II lupus nephritis be treated as dictated by the extrarenal clinical manifestations of lupus Class III is mild to treat non-renal manifestations, severe be treated as classe IV Class IV, V be treated with immunosuppressants can choose the following drugs: Prednislone, Cyclophosphamide, Methylprednison pulse dose, AzA, CsA, MMF, Rituximab, Plasma exchange Class VI is not indicated for immunosuppressant therapy, alternative treatment such as dialysis, kidney transplantation • Protocol for patients without renal biopsy: Patients with clinical symptoms of lupus nephritis but only minor urine disorders: proteinuria less than 1g/24 hours, no erythrocytes or erythrocytes less, treatment mainly extrarenal clinical manifestations of lupus Patients with acute glomerular syndrome: be treated by an immunosuppressant medication as in the protocol for patients with renal biopsy 4.2.2 The treatment lupus nephritis by MMF The origin and development MMF • MMF has the chemical name ester 2-morpholioethyl mycophenolic acid (MPA), isolated from Penicillium in the early 1896s and refined in 1913 In 1940 MPA was known as an antibacterial and antifungal agent In the late 1960s MPA was shown to play a role in inhibiting tumor cell proliferation, and by 1987 MPA was shown to play a role in anti-rejection transplantation and was approved by the FDA for the designation of transplant rejection in 1995 filter inosine monophosphate dehydrogenase thereby inhibiting the nucleotide nucleoside synthesis of guanosine, inhibiting the maturation and development of B and T lymphocytes The indication of MMF for patients with SLE EULAR- 2019 recommendation of MMF from mild to severe SLE without renal manifestations The indication of MMF for patients with lupus nephritis About a decade ago, MMF was considered an optimal option for the treatment of lupus nephritis, both in its effectiveness and safety, and is one of only two drugs recommended by the ACR for induction treatment lupus nephritis class III and class IV, and class V Chapter 2: SUBJECT AND METHOD OF THE STUDY Subject of the study 56 patients were diagnosed with lupus nephritis by clinical expert and renal biopsy and be treated by MMF with dose 2g per day at the Center of Allergic and Clinical Immunology, Bach Mai Hospital from August 8, 2015 to June /2018 was enrolled this study Study inclusion patients: be selected for study, the patients must meet all of the following criteria: • All patients were diagnosed with lupus nephritis by clinical expert and renal biopsy and be treated by MMF with dose 2g per day at the Center of Allergic and Clinical Immunology, Bach Mai Hospital • All gender patients age from 15 to 70 years at the time of the study • Femal patients of childbearing age must be contraception − − − − − − Study exclusion criteria: be exluded from the study if any of the following exclusion criteria exist The patients who not meet the patient selection criteria The patients who are taking other effective immunosuppressant The patients who are pregnant The patients with severe infections, malignancies such as caner The patiets with a history of hypersensitivity to any component of MMF The patient disagrees following the study Method of study Design of study Study open label, describe retrospective study, compare before and after treatment Sample size: By the convenient clinical sample size, the total number of patients participating in the study Method of collection date: 10 All patient information was collected on a consistent study format at the time of study and every weeks of treatment extended to week 24 Indication MMF for patients with lupus nephritis • The patients were class III, IV, V lupus nephritis in renal biopsy • The patients were diagnosed lupus nephritis by clinical without renal biopsy, who be indicated MMF by expert Indication stop taking MMF in patients with lupus nephritis • The patients who have side effect after taking MMF such as neutropenia, severe infections • The patients who not agree to continue taking MMF The protocol of therapy: Following the guideline of ACR − Methylprednisonlone vial 500mg intravenous time/ day in days After that tapering 1mg/kg/day, continue tapering 4mg/ week until the maintain dose 8mg/days − Hydroxycloroquine dose 200mg/day − Mycophenolate moferil dose 2g/day − Losartan dose50mg/ day − IV albumine, diuretics, Blood infusion as need Describe the process of study Patients were examined and evaluated clinical and laboratory indicators according to the criteria in the protocol of study, adverse events during treatment at the first time of the study and after every weeks of follow-up visits, 24 weeks after treatment Evaluation the response of treatment Assess the level of response to treatment after months and months • Completed response if the patients meet all of criterias following: − Proteinuria 24 hours after treatment < 0,5g/24 hours − GFR after treatment > 60ml/minutes • Partial response if the patients meet all of criteria following − Proteinuria 24 hours after treatment reduce > 50% compare with proteinuria before treatment − Proteinuria 24 hours after treatment < 3,5g/24 hours − Stabilization of GFR ± 25% of baseline or implovement • Non-response if the patients not meet completed and partical respone criteria Safety assessment Physical examination to detect symptoms due to side effects of the drug such as drug allergy, zoster infection 13 Chart 3.2: Renal disorder baseline More than 40% of patients with lupus nephritis have decerase of GFR Chart 3.3: Laboratory of blood baseline of patients with lupus nephritis Hypoalbuminemia and dyslipidemia met more than 70% of patients in both groups Hepatic dysfunction manifested in three GOT, GPT and GGT were observed in more than 20% in both patient groups Table 3.8 Laboratory of urine baseline of patients with lupus nephritis Total of patients Renal biopsy patients Numbe x̅ ± SD, % x̅ ± SD, % Number Proteinuria 24 hours (g/24h) r 56 4,14 ± 4,36 38 5,03 ± 4,88 Albumine < 30g/l Dyslipedemia GOThigh >37(U/L) GPTpatient > 41(U/L) GGT > 61(U/L) The mean proteinuria 24 hours was in both groups Total patients Renal biopsy 14 1.3 Disorder of immune laboratory Chart 3.4 The prevalence of complement baseline It was observed that low C3 is more common low C4 in both of group patients Chart 3.6 Characteristics of immunological disorder baseline The ANA positive was observed in all patients group 96,2% and 94,4% C and C4 patients repectively The anti-dsDNA positive, Sm Decrease and antiphospholipid antibodies were observed Totallower patients 1.4 International Society of Nephrology-Renal Pathology Society Renal biopsy Classification of patients with lupus nephritis Chart 3.7 Classification of renal biopsy by ISN/RPS Biopsies from 38 patients was observed class III (50%), class IV (29%), class V (10,5%) The results of patient with lupus nephritis after treatment by MMF 2.1 The improvement of patients after treatment Table 3.15 The SLEDAI score pre-treatment and after months treatment Chỉ số SLEDAI Pre-treatment After treament P (n=38) months (n=38) x̅ ± SD 21,74 ± 5,60 8,05 ± 3,82 6,1(n=23) 72,7 57,7 (n=37) x̅ ± SD 7,89 ± 3,99 5,56 ± 2,92 < 0,001 Creatinin ≥ 90(n=25) 78,1 0,06 < 90(n=11) 21,9 100 15 (mmol/l) x̅ ± SD 93,61 ± 67,05 73,25 ± 43,13 0,001 (n=36) GFR ≥ 60(n=27) 81,8 0,012 < 60(n=9) 100 18,2 (ml/phút) x̅ ± SD 78,77± 29,62 93,79 ± 26,26 P
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