Study on the immune modification and effectiveness of treatment in patients with lupus nephritis after induction treatment with mycophenolate mofetil

Our study was observed the results compared to other authors in the country, as well as abroad, showed differences, but there were similarities in common features such as arthritis, malar rash, haematological disorders, positive for ANA antibodies, anti-dsDNA antibodies. Through this result, we have a better understanding of the diversity, as well as the complexity of disease manifestations in SLE patients in general and in patients with lupus nephritis in particular. Most patients will not have the full range of manifestations at the time of onset, and this is a challenge for us when wanting to diagnose and treat patients early. Therefore, patients who suspect SLE diagnosis should be monitored and re-evaluated regularly, so as not to miss or make a late diagnosis.

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ed 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. 4. 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 1. 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 6 /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 do 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. 2. 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: All patient information was collected on a consistent study format at the time of study and every 4 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 do not agree to continue taking MMF. The protocol of therapy: Following the guideline of ACR Methylprednisonlone vial 500mg intravenous 1 time/ day in 3 days. After that tapering 1mg/kg/day, continue tapering 4mg/ 1 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. 3. 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 4 weeks of follow-up visits, 24 weeks after treatment. 4. Evaluation the response of treatment Assess the level of response to treatment after 3 months and 6 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 do not meet completed and partical respone criteria. 5. Safety assessment Physical examination to detect symptoms due to side effects of the drug such as drug allergy, zoster infection ... Blood tests and urine analysis are taken at each scheduled visit described in the study process to detect drug side effects. 6. The ethics of study This is descriptive study, voluntary participants to study. Make sure to provide complete and appropriate information to each study subject. 7. Data analysis Using SPSS 20.0 statistical software. Chapter 3: RESULTS OF STUDY 1. Characteritis of patients 1.1. Characteristics of age and gender. Table 3.1. characteristics of age and gender. Total of patients (n=56) Renal biopsy patients (n=38) Number %, x̅ ± SD Number %, x̅ ± SD age 56 30,21 ± 10,68 38 31,24 ± 12,41 < 20 7 12,5 6 15,8 20-39 43 76,7 27 71,1 >40 6 10,8 5 13,2 Gender Men 5 8,9 3 7,9 Femal 51 91,1 35 92,1 Total 56 100 38 100 Characteristics of age and gender of all patients: - Most patients were aged under 40 years old (89,2%), the mean age is 30,21 ± 10,68(years). Mostly women (91,1%). Characteristics of age and gender of renal biopsy patients: - Most patients were aged under 40 years old (86,8%), the mean age is 31,24 ± 12,41 (years). Mostly women (92,1%). Table 3.3. SLEDAI score of patients with lupus nephritis SLEDAI score Total of patients (n=56) Renal biopsy patients n1=54 % n2=36 % Mild active (< 5 (điểm) 0 0 0 0 Medium active (5-10 điểm) 4 7,4 2 5,6 Severe active (> 10 điểm) 50 92,6 34 94,4 Mean SLEDAI 20,7 ± 6,2 (score) 20,58 ± 6,46 (score) n1 total of patients n2 number of patients were renal biopsy Characteristics of SLEDAI score in group of total patients with lupus nephritis. Most patients have SLEDAI score were severe active (92,6%). Mean SLEDAI is 20,7 ± 6,2 (score). Characteristics of SLEDAI score in group of renal biopsy patients. Most patients have SLEDAI score were severe active (94,4%). Mean SLEDAI is 20,58 ± 6,46 (score). Table 3.4. Baseline characteristics of patients lupus nephritis follow ACR 1997 STT Manifestations Total of patients (n=56) Renal biopsy patients (n=38) number % Number % 1 Malar rash 23 41,1 14 36,8 2 Discoid rash 1 1,8 0 0 3 photosensitivity 5 8,9 3 7,9 4 Oral ulcers 14 25 8 21,1 5 Non-erosive arthritis 34 60,7 22 57,9 6 Pleuritis or pericarditis (n1=30/n2=21) 13 43,3 12 57,1 7 Renal disorder 56 100 38 100 8 Neurological disorder 4 7,2 1 2,6 9 Haematological disorder (n1=54/n2=37) 36 66,7 25 67,6 10 antibody ANA(n1=53/n2=36) 51 96,2 34 94,4 11 Antibody ds-DNA (n1=53/n2=36) 40 75,5 25 69,4 n1 total of patients n2 number of patients were renal biopsy In both groups of patients evaluated, patients with lupus nephritis have diverse damage of organ tissue, accounting for the highest proportion are arthritis lesions, hematological disorders and serositis. 1.2. Paraclinical disorder of patients Chart 3.1: Haematological disorder baseline of patients. The prevalence of anemia patients was common in the group of biopsy patients and the total number of patients studied was 83.8% and 77.8%, respectively. The prevalence of patients with reduced leucopaenia is not high, just over 20%. However, nearly 70% of patients had lymphopenia in both groups. Nearly 20% of patients had thrombocytopenia below 100 G /l in both groups. Chart 3.2: Renal disorder baseline More than 40% of patients with lupus nephritis have decerase of GFR. Renal biopsy Total patients Albumine 37(U/L) GPT > 41(U/L) GGT > 61(U/L) 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 Proteinuria 24 hours (g/24h) Number x̅ ± SD, % Number x̅ ± SD, % 56 4,14 ± 4,36 38 5,03 ± 4,88 The mean proteinuria 24 hours was high in both patient groups. 1.3. Disorder of immune laboratory. Decrease C 3 and C4 Total patients Renal biopsy 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% patients repectively. The anti-dsDNA positive, Sm and antiphospholipid antibodies were observed lower. 1.4. International Society of Nephrology-Renal Pathology Society 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%). 2. 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 6 months treatment Chỉ số SLEDAI Pre-treatment (n=38) After treament 6 months (n=38) P x̅ ± SD 21,74 ± 5,60 8,05 ± 3,82 <0,001 The mean SLEDAI score decrease significant after treatment, p < 0,001. 2.2. The improvement of haematology disorder after treatment. Chart 3.11. The percentage of haematology disorder after treatment The percentage of patients with anemia, leukopenia, and thrombocytopenia improved significantly after 3 and 6 months of treatment. Especially no patients with thrombocytopenia after 6 months of treatment. 2.3. The change of laboratory after treatment Table 3.19. the change of kidney function after 6 months treatment Renal function Pre-treatment (%, x̅ ± SD) After treament 6 months (%, x̅ ± SD) P Ure (mmol/l) (n=37) ≤ 6,1(n=14) 27,3 42,3 0,477 > 6,1(n=23) 72,7 57,7 x̅ ± SD 7,89 ± 3,99 5,56 ± 2,92 < 0,001 Creatinin (mmol/l) (n=36) ≥ 90(n=25) 78,1 0 0,06 < 90(n=11) 21,9 100 x̅ ± SD 93,61 ± 67,05 73,25 ± 43,13 0,001 GFR (ml/phút) (n=36) ≥ 60(n=27) 0 81,8 0,012 < 60(n=9) 100 18,2 x̅ ± SD 78,77± 29,62 93,79 ± 26,26 P<0,001 The mean value of urea, creatinine and glomerular filtration rate improved markedly after treatment, the difference was statistically significant, p < 0,05. Table 3.22. The change of albumin ater each 4 weeks treatment Albumin Pre-treatment, x̅ ± SD After 4 weeks (n=40), x̅ ± SD After 8 weeks (n=37), x̅ ± SD After 12 weeks (n=36), x̅ ± SD After 16 weeks (n=26), x̅ ± SD After 20 weeks (n=26), x̅ ± SD After 24 weeks (n=35), x̅ ± SD Albumin máu(g/l) 27,74 ± 5,80 33,91 ± 6,39 34,36 ± 5,55 37,40 ± 5,44 36,77 ± 7,37 38,48 ± 5,17 39,17 ± 6,12 P after/ before treatment <0,001 <0,001 <0,001 <0,001 <0,001 <0,001 The mean of albumin values ​​increased significantly after 4 weeks of treatment and continued to increase after 6 months of treatment, p <0.05. 2.4. The change of proteinuria 24 hours after treatment Tabe 3.25. The chane of proteinuria 24 hours after treatment Proteinuria 24 hours Pre-treatment, x̅ ± SD After 4 weeks (n=28), x̅ ± SD After 8 weeks (n=25), x̅ ± SD After 12 weeks (n=42), x̅ ± SD After 16 weeks (n=26), x̅ ± SD After 20 weeks (n=26), x̅ ± SD After 24 weeks (n=38), x̅ ± SD Proteinuria 24 hours (g/24h) 4,40 ± 4, 79 2,35 ± 3,14 2,31 ± 2,96 1,05 ± 1,28 1,24 ± 1,89 1,25 ± 2,26 1,04 ± 1,68 P after/ before treatment 0,002 0,006 <0,001 <0,001 <0,001 <0,001 The mean 24-hour proteinuria decreased significantly after 4 weeks of treatment, and continued to decrease until week 24, p <0.05. 2.5. The change of complement after treatment Table 3.28. The change of complement after 6 months treatment Complement Pre-treatment x̅ ± SD After - treament 6 months x̅ ± SD P C3 (g/l), (n=23) 0,555 ± 0,288 0,844 ± 0,299 0,002 C4 (g/l), (n=23) 0,095 ± 0,083 0,276 ± 0,389 0,022 The mean values ​​of complement C3 and C4 both increased after treatment, p <0.05. 2.6. The change of autoantibodies after treament Chart 3.12. The change of percentage of ANA positive after treatment The percentage of patients with positive ANA antibodies decreased gradually after 3 months and 6 months of treatment, 93.7% and 82.9%, respectively. Chart 3.13. The change of percentage of anti-dsDNA positive after treatment The percentage of patients who tested positive for anti-dsDNA antibodies decreased gradually after 3 and 6 months of treatment, respectively 70.7% and 25.7%. 3. The effective of induction therapy lupus nephritis was indicated MMF and the relationship with immune modificactions. 3.1. The effective of induction therapy lupus nephritis by MMF Chart 3.9. The percentage of response after 3 moths and 6 months treatment After 3 months the percentage of response was 83,4%. After 6 months the percentage of response was 89,5%. 3.2 The assess factors associated with response to treatment Table 3.38. The relationship between SLEDAI score with response after 6 months of treatment SLEDAI score Response treatment (%) OR (95%CI) P SLEIDAI (score) <10 (n=2) 50,0 0,091 (0,004-1,850) 0,202 ≥10 (n=36) 91,7 The SLEDAI activity index was not correlated with the response after 6 months with p> 0.05. Table 3.42. The relationship between GFR with response after 6 months of treatment Biến số Response treatment (%) OR (95%CI) P GFR <60ml/minute (n=9) 100 0,862 (0,745-0,997) 0,554 ≥60ml/ minute (n=29) 86,2 The GFR was not correlated with the response after 6 months with p> 0.05. Table 3.46. The relationship between antibodies with response after 6 months of treatment Biến số Response treatment (%) OR (95%CI) P Antibody anti- dsDNA positive (n=30) 93,3 5,600 (0,634-49,477) 0,155 negative (n=7) 71,4 antibody Sm positive (n=4) 100 0,833 (0,647-1,073) 1 negative (n=12) 83,3 Anti-phospholipid positive (n=8) 87,5 0,636 (0,034-11,909) 1 negative (n=12) 91,7 The antibody anti-dsDNA, Sm, Anti-phosphoilipid were not correlated with the response after 6 months with p> 0.05. Table 3.48. The relationship between proteinuria 24 hours with response after 6 months of treatment Proteinuria 24 hours Response treatment (%) OR (95%CI) P Proteinuria 24 hours (g/24h) ≥ 3,5 (n=13) 92,3 1,636 (0,153-17,504) 1 < 3,5 (n=25) 88 The proteinuria 24 hours was not correlated with the response after 6 months with p> 0.05. Chapter 4: DISCUSSION 1. The characteristics of patients with lupus nephritis before treatment Characteristics of age and gender. We conducted research on 56 patients diagnosed with lupus nephritis at the Center of Allergy and Clinical immunology Bach Mai Hospital from May 2015 to June 2018. Of which 42 patients followed the protocol of study treatment after 12 weeks accounted for 75% and 38 patients followed the 24-week accounted for 67.86%. In our study group, the youngest patients are 15 years old, the oldest patients are 69 years old, the average age is 30.21 ± 10.68 (years old), the age group accounting for the highest proportion is the age group. under 40 years old with the rate of 89.2%. The most common age group for systemic lupus erythematosus is the reproductive age group, which is explained by many factors, but the most powerful factor is the change in estrogen hormone and prolactin during puberty and childbirth triggers the disease, in which androgens have a protective effect. The male to female ratio in our study is 1: 10.2. Gender and especially sex hormones play an important role in the formation and development of organ systems throughout life. The influence of sex hormones on the immune system is profound and lasting because they control the growth and differentiation of many immune-competent cells and if this control is flawed despite the level of molecule is enough to cause a disease. The SLEDAI score in lupus nephritis. Our study also assessed disease activity level based on SLEDAI score and we were observed the mean of SLEDAI-2K is 20.7 ± 6.2 (points), and mostly acute exacerbations active (SLEDAI). -2K > 10 points) (92.6%) and especially no patient in the inactive state (SLEDAI-2K <5 points). This can be logically explained that on a SLEDAI-2K score with a total score of 105, there are up to 4 signs of kidney damage, with each sign being 4 points, so for patients with lupus nephritis, the mean score can be nearly 16 points, even without the additional signs of other organs and systems. Characteristics of patient by ACR 1997 before treatment Our study was observed the results compared to other authors in the country, as well as abroad, showed differences, but there were similarities in common features such as arthritis, malar rash, haematological disorders, positive for ANA antibodies, anti-dsDNA antibodies. Through this result, we have a better understanding of the diversity, as well as the complexity of disease manifestations in SLE patients in general and in patients with lupus nephritis in particular. Most patients will not have the full range of manifestations at the time of onset, and this is a challenge for us when wanting to diagnose and treat patients early. Therefore, patients who suspect SLE diagnosis should be monitored and re-evaluated regularly, so as not to miss or make a late diagnosis. Characteristics of haematological tests. RBC characteristics: Our study shows the mean erythrocytes is 3.51 ± 0.83 (T / L), the mean hemoglobin is 100.4 ± 21.4 (g/l), and up to 77.8% of patients with hemoglobin levels below 120 (g/l). Pham Huy Thong et al studied over 30 patients with lupus nephritis showed that the mean erythrocytes were 3.79 ± 0.79 (T/l), the mean hemoglobin was 99.94 ± 17,29 (g/l). Do Thi Lieu et al studied 125 patients with lupus nephritis at Bach Mai Hospital, showing that 82.3% of patients had a decrease in the number of red blood cells. Leukocyte characteristics: In our study of 22.2% of patients with leukopenia, of which neutropenia was 14.8% and lymphopenia by 66.7%, we would like to emphasize The question of why the total leukopenia rate is only 22.2%, and the lymphopenia rate decreases to 66.7%, which is an important feature that should not be overlooked when evaluating hematological tests. In patients with systemic lupus erythematosus, sometimes we just observe the total number of leukocyte and forget to evaluate each specific leukocyte component for each disease, as here, the lymphopenia is a characteristic feature manifestation of SLE, more than total leukopenia. Platelet characteristics: Our study found 18.5% of patients with thrombocytopenia below 100 (G/l) according to ACR 1997 standards. Tran Van Vu et al Lupus nephritis patients showed that 21.76% of patients with thrombocytopenia below 100 (G/l). The results of this study are completely in accordance with the data synthesized previously. The characteristics of blood biochemical test. The characteristics of kidney function: Our results show that up to 40.7% of patients with glomerular filtration rate fall below 60 (ml/min). Do Thi Lieu et al studied 89 patients diagnosed with lupus nephritis at Bach Mai Hospital from 1992 to 1998, resulting in 49.4% of patients with acute renal failure. Vuong Tuyet Mai et al Investigated a number of factors related to changes in glomerular filtration rate over time in patients with lupus nephritis during inpatient treatments in 44 patients showing glomerular filtration rate decreased kidney function, especially between decreased glomerular filtration rate and hypoalbuminemia. Because our study and Vuong Tuyet Mai used different formula for calculating glomerular filtration rate, it could not be directly compared, but both studies showed a decrease in glomerular filtration rate in patients lupus nephritis. The characteristics of albumine: Our results show that 66% of patients have hypoalbuminemia below 30 (g/l). Tran Van Vu et al studied 170 patients with lupus nephritis found that 80.59% of patients with lupus nephritis had a decrease in serum albumin below 25 (g/l). Hypoalbuminemia is reported in most published studies. The characteristics of urine test: Our study showed that the mean 24-hour proteinuria was 4.14 ± 4.36 (g/24 hours). Our mean proteinuria was higher than that of Suchitha Satish et al a study of 56 patients with lupus nephritis with the mean 24-hour proteinuria of 2.00 ± 1,502 (g/24 hours), Nasri et al studied 84 patients with lupus nephritis with 24-hour proteinuria of 1.6 ± 1.9 (g/24 hours). Our research results are also consistent with those reported in the literature. The characteristics of complement: Our study found that 90.6% of patients decreased C3 below 0.9 (g/l), patients decreased C4 below 0.1 (g/l). Tran Van Vu et al studied 170 patients with lupus nephritis showed that 98.82% of patients with C3 decreased and C4 patients had 88.24%. We can see that there is not much difference between our study and domestic and foreign authors, however, it can be seen that C3 and C4 decreases are high in lupus nephritis patients in most studies. This is why C3 and C4 are included in the SLEDAI index. The characteristics of antibody ANA test. Our results are also higher than those reported by a number of other national authors. However, our study results are similar to those of other authors recently reported and consistent with the literature, which reported that over 95% of lupus patients were positive for ANA antibodies, which could be explained by the same testing methods, as well as testing techniques have improved significantly in recent years. Our research results are similar to some studies of foreign authors. The characteristics of antibody anti-dsDNA test. Our study found that 75.5% of patients were positive for dsDNA antibodies, consistent with the report reporte

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