MILITARY MEDICAL UNIVERSITYHUYNH VAN KHOA CHARACTERISTICS OF IMMUNE DISORDERS AND RESULTS OF PULSE METHYLPREDNISOLONE THERAPY IN SEVERE SYSTEMIC LUPUS... Systemic lupus erythematosus is
Trang 1MILITARY MEDICAL UNIVERSITY
HUYNH VAN KHOA
CHARACTERISTICS OF IMMUNE DISORDERS AND RESULTS OF PULSE METHYLPREDNISOLONE THERAPY IN
SEVERE SYSTEMIC LUPUS
Trang 2MILITARY MEDICAL UNIVERSITY
Full name of supervisor:
1 Associate Pr LE ANH THU
2 Associate Pr LE THU HA
Review 1: Associate Pr Nguyen Dang Dung
Review 2: Associate Pr Phan Quang Doan
Review 3: Associate Pr Dang Hong Hoa
The dissertation will be protected before the Board of thesis
dissertation at the Military Medical University
By the day month year
Can study thesis at
- National Library of Vietnam
- Library of Military Medical University
Trang 3Systemic lupus erythematosus is a chronic disease characterized
by a wide variety of clinical manifestations characterized by theproduction of autoantibodies that cause disorders of the immune system.Systemic lupus erythematosus can occur at any age, including childrenand older adults, but the incidence rate of women suffering from thedisease accounts for 90% of the cases
Clinical manifestations of the progression of the disease areusually in the skin, joints, hematology, organ damage (kidney,cardiovascular, respiratory .) Severe internal organ damage is thedirect or indirect cause of death The use of high-dose intravenous (pulsetherapy) methylprednisolone for cases of flare severe systemic lupuserythematosus life-threatening and many studies have shown to beeffective
In Vietnam, there are no studies that adequately assess theefficacy and safety of this therapy, especially in cases where lupus is aprogressive multiorgan lesion So we conducted this study with thefollowing objectives:
1 Study some characteristics of immune disorders, analysis ofassociation with target organ damage and activity level (SLEDAI score)
in patients with severe systemic lupus erythematosus
2 Evaluation of treatment outcome of pulsed methylprednisolonetherapy combined with baseline treatment after 12 weeks in patients withsevere systemic lupus erythematosus
Thesis structure
The thesis has: forewords (3 pages), chapter 1: overview (40pages), chapter 2: research subjects and methods (19 pages),chapter 3: research results (36 pages), chapters 4: Discussion(30 pages), and conclusions (2 pages), Recommendations (1page)
In the thesis there are: 48 tables, 5 graphs, 2 diagrams
The thesis has 167 references, including 16 in Vietnamese, 150
in English, 1 French
Trang 4CHAPTER 1- OVERVIEW 1.1 Autoimmune antibodies
The autoimmune antibodies and their pathological evidence inpatients with lupus are described in the table below:
specific antibody Frequency % Main clinical manifestations
Anti-dsDNA 70 -80 Kidney, skin
Anti –Nucleosome 60- 90 Kidney, skin
Anti- Ro 30- 40 Skin, kidneys,
Fetal cardiovascular problemAnti – La 15 -20 Fetal cardiovascular problemAnti – Sm 10-30 Kidney disease
Anti-NMDA receptor 33- 50 Encephalopathy
Anti–Phospholipid 20- 30 Circumcision, miscarriageAnti -α Actinin 20 Kidney disease
Anti - C1q 40- 50 Kidney disease
1.2 Immune characteristics in patients with SLE
Reduction of C3, C4 complement is a common manifestation oflupus erythematosus The disorder of the immunoglobulin in patientswith SLE is very diverse and depends on the level of activity of thedisease
1.3 Evaluations of progression and severe SLE manifestations
1.3.1 SLEDAI (Systemic Lupus Erythematosus Disease Activity Index)
SLEDAI reviews consist of 24 components.
SLEDAI scores range from 0 to 105 points
Seizure, psychosis, organic brain syndrome, visual
disurbance, neuropathy involving a cranial nerve, lupus
headache, cerebrovascular accident, vasculitis
Trang 5Evalation process value by SLEDAI
SLEDAI score Activity level
SLEDAI = 0 Not active
SLEDAI 1 – 5 minor active
SLEDAI 6-10 Average active
SLEDAI 11-19 Severe active
SLEDAI 20 Very severe active
1.3.2 Evaluation of severe organ damage
Lupus nephritis had nephrotic syndrome, reduced creatinineclearance> 25% during 3 months of follow-up Proteinuria> 2g /day for 3 months of follow-up, glomerulonephritis progressingrapidly
Severe autoimmune hemolysis (Hb <7g / dl and Coombs test orScreening test (+)), severe thrombocytopenia <50 G / l and noresponse to high dose corticosteroid therapy
There are neurological or psychiatric disorders and there isevidence of brain damage on MRI
Interstitial lung disease, alveolar hemorrhage
Myocarditis
Optic neuritis, retinal hemorrhage, multiple organ damagesimultaneously
1.4 Treatment of severe SLE
In many severe SLE, corticosteroid basic doses do not respond
to treatment Pulse Methylprednisolone (MP) therapy is usuallyindicated with or without other immunosuppressive agents
1.5 Mechanism active of Corticosteroid in SLE
Mechanism of action of corticosteroids in autoimmune diseasethrough 2 processes is anti-inflammatory and immunosuppressive.Corticosteroids inhibit the following: lymphocyte, neutrophil,monocyte, IL-1-stimulated T cells, B-cell transformations, IgGproduction, bioactive monocytes, cytokine production
Intravenous hight dose corticosteroid therapy (pulse MP): Usuallyused with very high doses of methylprednisolone (250-1000 mg)intravenously for 3 consecutive days This therapy is usuallyprescribed for severe SLE
Trang 61.6 Research for the pulse MP
De Glas-Vos JW and colleagues studied pulse MP for severe lupusnephritis
Kovacs, Trevisani studied pulse MP lupus erythematosus with CNSinvolvement
Isenberg and colleagues studied the pulse MP for lupus activity
Doan Van De studied pulse MP for severe lupus
Pham Huy Thong studied pulse MP for severe lupus nephritis
CHAPTER 2- SUBJECTS AND METHODS OF THE STUDY 2.1 SUBJECTS OF THE STUDY
2.1.1 Subjects of study: 112 patients were diagnosed with systemic
lupus erythematosis based on ACR criteria in 1997 and showed severeprogression was treated and monitored at Cho Ray hospital in HCMCfrom May/ 2011 through December 2015 80 patients in 112 patientsreceived pulse MP
2.1.2 Criteria for selecting patients
SLE diagnosis according ACR 1997
Severe SLE diagnosis according to Petri M
SLEDAI scores ≥ 12 points
And at least one of the internal organs is damaged as follows:
Lupus nephritis with nephrotic syndrome: edema, proteinuria ≥ 3.5
g / 24 hours, hypoalbuminemia, hyperlipidemia
Lupus with central nervous system (CNS) involvement: Clinicalmanifestations of central nervous system invovement and cerebralMRI have typical brain lesions due to lupus Eliminate neurologicalmanifestations caused by other causes
Severe anemia due to autoimmune hemolysis: Hb <7 g / dl anddirect Coombs (+) or screening test with presence of autoantibody
Severe pulmonary lesions due to lupus: haemorrage alveola orinterstitial pneumonitis due to lupus, not due to bacterial infection ortuberculosis
Acute myocarditis due to lupus
Trang 72.1.3 Exclusion criteria
Patients with systemic lupus erythematosus are progressing but are not eligible for pulsed methylprednisolone therapy
Patients with contraindication for pulse MP: peptic ulcer
progressive, diabetes mellitus, poor contral hypertension, patients with severe electrolyte disturbances, severe glaucoma, patients pregnant
Patients are using other immunosuppressive drugs
Patients with severe infection or progressive TB
2.2 METHODS OF THE STUDY
2.2.1 study design
Descriptive study, cross-sectional, longitudinal follow-upcomparisons and post-treatment to evaluate treatment outcomes.collection patients convenience over time
Select patients who are eligible for treatment for pulse MP therapy
2.2.3 Laboratory testing and evaluation of results
2.2.3.1 Hematological tests
Peripheral blood count, rate of blood sedimentation, Coombstests, Screening tests were performed at Cho Ray Hospital Test resultsand hematological assessment are recognized in accordance with ISO15189: 2012
2.2.3.2 Routine biochemical tests
2.2.3.3 Urine test
2.2.3.4 Autoimmune antibodies tests
ANA tests were performed at the Hematological Center andother autoimmune antibodies: anti-dsDNA, anti-Sm, anti-SSA (Ro),anti-SSB (La) Cho Ray Test results are also recognized in accordancewith ISO 15189: 2012
2.2.3.5 Tests for C3, C4 and immunoglobulin
2.2.3.6 Tests for the cytokines TFNA, IL6, IL10
Trang 82.2.4 Treatment regimen
Pulse MP therapy: Patients were treated with 1 g
methylprednisolone (MP) / day as recommended by the AmericanRheumatology Association, which was administered for 3 consecutivedays Methylprednisolone 1 g diluted in 100 ml sodium and infusionintravenous for 1 hour, the patient is monitored by monitor Patients areclosely monitored clinically: pulse, heat, blood pressure, weight, urine /
24 hours, monitoring of cardiac, pulmonary, digestive and full status.Management of side effects may occur during and after pulse MP.Treatment basic: After MP therapy, patients continued to receiveMethylprednislone 1mg / kg / day orally, Hydoxychloroquine, and othermedications: hypotension, calcium-D, potassium supplementation ,medications for symptomatic relief and other prophylaxis if needed.Evaluate the response to treatment and follow-up of side effects at thetime of the visit according to the study sample
2.2.5 Result evaluation
Evaluation of immune dysfunction in 112 severe SLE patients
Evaluation of treatment response based on changes in anti-dsDNAantibody levels before and after treatment for 1 week, 4 weeks and
12 weeks
Evaluation of treatment response based on changes in C3, C4, Ig
MD before and after MP treatment 1 week, 4 weeks and after 12weeks
Evaluation of treatment response was based on changes in cytokineTNFA, IL6, IL 10 before and after MP treatment for 1 week and 4weeks
Overall treatment response was based on SLEDAI changes beforeand after treatment at 1 week, 4 weeks and 12 weeks, and dividedthe response based on SLEDAI score of decline according to ACR
For lupus nephritis with syndrome nephrotic , we evaluated theresponse based on the Kedney Disease Improving Global Outcomes
(KDIGO 2012) guidelines as follows: Complete response:
Proteinuria <0, 5 g / 24h, blood albumin ≥ 3 g / dL, GFR> 60 ml /min or improvement of eGFR> 50% vs pretreatment, no red blood
cell, urolith Partial response: Reduction in creatinine clearance>
50% vs pretreatment, blood serum albumin <3 g / dL and
improvement of eGFR> 50% vs pretreatment Not responding: Proteinuria> 3g / 24h, decreased urinary protein <50% compared
Trang 9with before treatment, reduced eGFR <20% compared with treatment.
pre-2.2.7 Study diagram
112 severe SLE
80 patients treated with pulse MPCharacteristics of immune
disorders - Related analysis
Evaluation of pulse MP therapy efficacy
Report on study results
Clinical examination, tests and selection Patients are eligible critica for study
Trang 10CHAPTER 3- RESULTS OF THE STUDY
3.1 Distribution of patients by age and sex
The highest rates of patients in the age group of 20-29 years,accounting for 45.5%, for the age group of 20-39 years, accounting for68.2%, the majority femele accounting for 90.2%
3.2 Characteristics of immune disorders in severely SLE, associated with some immunological indices with organ damage and with the SLEDAI score.
3.2.1 Characteristics of immune disorders in severely SLE
3.2.1.1 Characteristics of autoimmune antibodies
Table 3.1 Characteristics of autoimmune antibodies
Trang 113.2.1.2 Characteristics of complements levels and immunoglobulins levels
Table 3.2 Characteristics of the complements levels and
IgE increase (n=95) 76 80.0IgG increase (n=109) 28 25.7IgM increase (n=109) 10 9.2C3 decrease rate was 94.6%, C4 decrease was 63.4%, IgE increased
80%
3.2.1.3 Characteristics of cytokine levels
Table 3.3 Characteristics of cytokine levels
Cytokine
Pg/mL
Number ofpatients
3.2.2 Relate some of the immunity indicators and organ damage
3.2.2.1 Autoimmune antibodies and organ demage
3.2.2.1.1 Autoimmune antibodies and kidney lesion
Trang 12Table 3.4 Comparison of serum antibodies levels between the presence
and absence of kidney lesion
Antibodies
Kidney lesion [Median (quartile)] P
Value
Have (n=86) Are not (n=26)
Anti-dsDNA UI/mL (n=112) 240.0 (78.63-240.0) 210.1(60.45-240) 0.436Anti-Cardiolipin IgM U/mL (n=103) 2.0 (2.0-2.98) 4.6 (2.0-6.4) 0.014
Anti-Cardiolipin IgG U/mL (n=103) 5.75 (2.0-21.98) 3.8 (2.8-12.7) 0.833Anti –Sm UI/mL (n=103) 6.35 (2.63-33.98) 18.8 (5.0-100) 0.021
Anti-SSA (Ro) UI/mL (n=100) 8.5 (2.1-100) 40.6 (2.8-100) 0.160Anti-SSB (La) UI/mL (n=100) 3.5 (1.1-5.85) 2.5 (1.3-6.2) 1The levels of anti-dsDNA were higher in the group with kidney lesionbut not statistically significant
3.2.2.1.2 Autoimmune antibodies and hematologic disorders
Table 3.5 Comparison of autoimmune antibody levels between and
without hematologic disorders
Antibodies
Hematological disorders [Median (quartile)] P
Value Have (n=90) Are not (n=22)
Anti-dsDNA UI/mL 240.0 (115.13-240.0) 59.05(24.95-239.90) <0.001Anti-Cardiolipin IgM U/mL 2.0 (2.0-4.6) 2.0 (2.00-3.83) 0.621Anti-Cardiolipin IgG U/mL 8,3 (2,3-29,6) 2.45 (2.00-3.60) 0.001
Anti –Sm UI/mL 7,0 (2,93-33,98) 18.8 (3.6-100.0) 0.336
Concentration levels of anti-dsDNA and anti-Cardiolipin IgG
were significantly higher (p <0.001 and p = 0.001) in the hematologic
disorder group than in the non-haematological disorder group
Trang 133.2.2.3 Relation of cytokine concentrations levels and organ damage 3.2.2.3.1 Cytokine concentrations levels and kidney lesion
Table 3.6 Comparison of cytokine concentrations levels between kidney
lesion group and without kidney lesion gruop
Cytokine
pg/mL
Kidney lesion [Median (quartile)] P Value have (n=86) Are not (n=26)
TNFA (n=94) 9.76 (6.82-17.45) 6.53 (4.49-13.86) 0.050IL6 (n=94) 11.05 (5.41-26.85) 17.61 (9.08-45.90) 0.221IL10 (n=94) 4.93 (2.88-9.17) 5.01 (3.10-9.17) 0.738TNFA levels in the kidney lesion group may be higher
3.2.2.3.2 Cytokine levels and hematologic disorders
Table 3.7 Comparison of cytokine levels between and without
hematologic disorders
Cytokine
pg/mL
Hematological disorders [Median (quartile)] P Value have (n=90) Are not (n=22)
TNFA (n=94) 9.97 (6.81-19.33) 6.42 (4.35-9.22) 0.024
IL6 (n=94) 14.39 (6.25-35.06) 10.25 (3.14-18.26) 0.149IL10 (n=94) 4.90 (2.87-9.21) 7.08 (3.69-9.12) 0.514There was a statistically significant difference (p = 0.024) in TNFAlevels between the two groups with haematological disorders and nohaematological disorders
3.2.2.3.3 Cytokine levels and CNS involvements
Table 3.8 Comparison of cytokine levels between the presence and
absence of CNS involvements
Cytokine
pg/mL
CNS lesions
[Median (quartile)] p value
have (n=32) Are not (n=80)
TNFA (n=94) 9.89 (7.58-17.87) 9.19 (6.14-17.04) 0.521IL6 (n=94) 18.26 (9.81-34.46) 11.73 (4.83-27.84) 0.192IL10 (n=94) 8.46 (4.69-11.58) 4.54 (2.37-8.51) 0.020There was a statistically significant difference (p = 0.020) in IL10 levelsbetween the two groups with CNS involvements and no CNS involve
3.3 Relation of autoimmune antibodies levels, complements,
immunoglobulins, cytokine and disease activity (SLEDAI)