TÓM tắt TIẾNG ANH đánh giá hiệu quả điệu trị bệnh nhân lupus ban đỏ hệ thống mức độ nặng bằng liệu pháp methylprednisolone xung

MINISTRY OF EDUCATION AND TRAINING

DEPARTMENT OF DEFENSE

MILITARY MEDICAL UNIVERSITY

HUYNH VAN KHOA

CHARACTERISTICS OF IMMUNE
DISORDERS AND RESULTS OF PULSE
METHYLPREDNISOLONE THERAPY IN
SEVERE SYSTEMIC LUPUS
ERYTHEMATOSUS
Specialization: Internal Medicine
Code: 9720107
SUMMARY OF DOCTORAL THESIS

HA NOI – 2018


THE THESIS WAS COMPLETED AT:
MILITARY 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


1
FOREWORDS
Systemic lupus erythematosus is a chronic disease characterized
by a wide variety of clinical manifestations characterized by the
production of autoantibodies that cause disorders of the immune system.
Systemic lupus erythematosus can occur at any age, including children
and older adults, but the incidence rate of women suffering from the
disease accounts for 90% of the cases.
Clinical manifestations of the progression of the disease are
usually in the skin, joints, hematology, organ damage (kidney,
cardiovascular, respiratory ...). Severe internal organ damage is the direct
or indirect cause of death. The use of high-dose intravenous (pulse
therapy) methylprednisolone for cases of flare severe systemic lupus
erythematosus life-threatening and many studies have shown to be
effective.
In Vietnam, there are no studies that adequately assess the
efficacy and safety of this therapy, especially in cases where lupus is a
progressive multiorgan lesion. So we conducted this study with the
following objectives:
1. Study some characteristics of immune disorders, analysis of

association with target organ damage and activity level (SLEDAI score)
in patients with severe systemic lupus erythematosus.
2. Evaluation of treatment outcome of pulsed methylprednisolone
therapy combined with baseline treatment after 12 weeks in patients with
severe systemic lupus erythematosus.
Thesis structure


The thesis has: forewords (3 pages), chapter 1: overview (40
pages), chapter 2: research subjects and methods (19 pages),
chapter 3: research results (36 pages), chapters 4: Discussion
(30 pages), and conclusions (2 pages), Recommendations (1
page)



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.


2
CHAPTER 1- OVERVIEW
1.1. Autoimmune antibodies
The autoimmune antibodies and their pathological evidence in
patients 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

Anti – La

15 -20

Skin, kidneys,
Fetal cardiovascular problem
Fetal cardiovascular problem

Anti – Sm

10-30

Kidney disease

Anti-NMDA receptor
Anti–Phospholipid

33- 50
20- 30

Encephalopathy
Circumcision, miscarriage

Anti -α Actinin
Anti - C1q

20

Kidney disease

40- 50

Kidney disease

1.2. Immune characteristics in patients with SLE
Reduction of C3, C4 complement is a common manifestation of
lupus erythematosus. The disorder of the immunoglobulin in patients
with SLE is very diverse and depends on the level of activity of the
disease.
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
Descriptor
Score
Seizure, psychosis, organic brain syndrome, visual
8
disurbance, neuropathy involving a cranial nerve, lupus
headache, cerebrovascular accident, vasculitis
Arthritis, Myositis, Casts, Hematuria, Proteinuria, Pyuria
4
New malar rash, alopecia, mucous membranes, pleurisy,
2
pericarditis, low complement, increased DNAbinding
Fever, thrombocytopenia, leukopenia
1


3
Evalation 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 creatinine
clearance> 25% during 3 months of follow-up. Proteinuria> 2g /
day for 3 months of follow-up, glomerulonephritis progressing
rapidly.
 Severe autoimmune hemolysis (Hb <7g / dl and Coombs test or
Screening test (+)), severe thrombocytopenia <50 G / l and no
response to high dose corticosteroid therapy.
 There are neurological or psychiatric disorders and there is
evidence of brain damage on MRI.
 Interstitial lung disease, alveolar hemorrhage
 Myocarditis
 Optic neuritis, retinal hemorrhage, multiple organ damage
simultaneously.
1.4. Treatment of severe SLE
In many severe SLE, corticosteroid basic doses do not respond
to treatment. Pulse Methylprednisolone (MP) therapy is usually

indicated with or without other immunosuppressive agents.
1.5. Mechanism active of Corticosteroid in SLE



Mechanism of action of corticosteroids in autoimmune disease
through 2 processes is anti-inflammatory and immunosuppressive.
Corticosteroids inhibit the following: lymphocyte, neutrophil,
monocyte, IL-1-stimulated T cells, B-cell transformations, IgG
production, bioactive monocytes, cytokine production .


4



Intravenous hight dose corticosteroid therapy (pulse MP): Usually
used with very high doses of methylprednisolone (250-1000 mg)
intravenously for 3 consecutive days. This therapy is usually
prescribed for severe SLE.
1.6. Research for the pulse MP
 De Glas-Vos JW and colleagues studied pulse MP for severe lupus
nephritis.
 Kovacs, Trevisani studied pulse MP lupus erythematosus with CNS
involvement.
 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 severe
progression was treated and monitored at Cho Ray hospital in HCMC
from May/ 2011 through December 2015. 80 patients in 112 patients
received 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: Clinical
manifestations of central nervous system invovement and cerebral
MRI have typical brain lesions due to lupus. Eliminate neurological
manifestations caused by other causes
 Severe anemia due to autoimmune hemolysis: Hb <7 g / dl and
direct Coombs (+) or screening test with presence of autoantibody.
 Severe pulmonary lesions due to lupus: haemorrage alveola or
interstitial pneumonitis due to lupus, not due to bacterial infection or
tuberculosis
 Acute myocarditis due to lupus.


5
2.1.3. 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-up
comparisons and post-treatment to evaluate treatment outcomes.
collection patients convenience over time.
2.2.2. Clinical visit
Each patient has a unified medical record according to the research
sample (Appendix 1)
 Patients admitted to the hospital were fully screened and evaluated
for clinical manifestations and laboratory tests in a consistent format
to determine the diagnosis of SLE and to assess the severity of the
SLE.
 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, Coombs
tests, Screening tests were performed at Cho Ray Hospital. Test results
and hematological assessment are recognized in accordance with ISO
15189: 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 and
other autoimmune antibodies: anti-dsDNA, anti-Sm, anti-SSA (Ro), antiSSB (La) Cho Ray. Test results are also recognized in accordance with
ISO 15189: 2012.
2.2.3.5. Tests for C3, C4 and immunoglobulin

6
2.2.3.6. Tests for the cytokines TFNA, IL6, IL10
2.2.4. Treatment regimen
Pulse MP therapy: Patients were treated with 1 g
methylprednisolone (MP) / day as recommended by the American
Rheumatology Association, which was administered for 3 consecutive
days. Methylprednisolone 1 g diluted in 100 ml sodium and infusion
intravenous for 1 hour, the patient is monitored by monitor. Patients are
closely 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 receive
Methylprednislone 1mg / kg / day orally, Hydoxychloroquine, and other
medications: 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 the
time 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-dsDNA
antibody 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 12
weeks.
 Evaluation of treatment response was based on changes in cytokine
TNFA, IL6, IL 10 before and after MP treatment for 1 week and 4
weeks.

 Overall treatment response was based on SLEDAI changes before
and after treatment at 1 week, 4 weeks and 12 weeks, and divided
the response based on SLEDAI score of decline according to ACR .



For lupus nephritis with syndrome nephrotic , we evaluated the
response 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


7
improvement of eGFR> 50% vs. pretreatment. Not responding: 
Proteinuria> 3g / 24h, decreased urinary protein <50% compared
with before treatment, reduced eGFR <20% compared with pretreatment.
2.2.7. Study diagram

Clinical examination, tests and selection
Patients are eligible critica for study

112 severe SLE

Characteristics of immune
disorders - Related analysis

80 patients treated with pulse MP

Evaluation of pulse MP therapy efficacy
after 1 week

Evaluation of pulse MP therapy efficacy
after 4 weeks

Evaluation of pulse MP therapy efficacy
after 12 weeks

Report on study results


8
CHAPTER 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 for
68.2%, 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
Autoimmune
antibodies (+)

Number of patients
(n=112)

Ratio %

ANA

110

98.2

Anti-dsDNA

89

79.5

Anti -Sm (n= 103)

44

42.7

Anti-Cardiolipin IgM (n=103)

7

6.8

Anti-Cardiolipin IgG (n=103)

28

27.2

Anti-SSA (Ro) (n=102)

52

51.0

Anti-SSB (La) (n=100)

13

13.0

The rate of ANA (+) was 98.2%, anti-dsDNA (+) was 79.5%,
anti-Sm was 42.7%.


9
3.2.1.2. Characteristics of complements levels and immunoglobulins
levels
Table 3.2. Characteristics of the complements levels and
immunoglobulins levels
Index immunoglobulins
Number of patients
Ratio %
(n=112)
C3 reduction (n=112)
106

94.6
C4 reduction (n=112)

71

63.4

IgA increase (n=109)
IgE increase (n=95)

9
76

8.3
80.0

IgG increase (n=109)
28
25.7
IgM increase (n=109)
10
9.2
C3 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
Number of
Ratio %
Pg/mL

patients
(n=112)
TNFA
Increase
38
40.4
Medium (min-max)
IL6

Increase
Medium (min-max)

IL10

Increase
Medium (min-max)

25.69 ± 67.45 (1.5 – 506)
90

95.7

53.16 ± 155.14 (0.43 – 1495)
80

85.1

24.64 ± 154.36 (0.02 – 1496)

TNFA increased 40.4%, IL6 increased 95.7% and IL10 increased 85.1%.

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


10
Table 3.4. Comparison of serum antibodies levels between the presence
and absence of kidney lesion
Kidney lesion
[Median (quartile)]

Antibodies

Have (n=86)
240.0 (78.63240.0)

Anti-dsDNA UI/mL (n=112)

P
Value

Are not
(n=26)
210.1(60.45240)

0.436

Anti-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)

0.833

Anti –Sm UI/mL (n=103)

6.35 (2.63-33.98)

18.8 (5.0-100)

0.021

8.5 (2.1-100)

40.6 (2.8-100)

0.160

Anti-SSA (Ro) UI/mL (n=100)

Anti-SSB (La) UI/mL (n=100)

3.5 (1.1-5.85)
2.5 (1.3-6.2)
The levels of anti-dsDNA were higher in the group with kidney lesion
but not statistically significant.

1

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)]
Have (n=90)

Anti-dsDNA UI/mL

240.0 (115.13240.0)

Are not (n=22)

P
Value

59.05(24.95-239.90)

<0.001

Anti-Cardiolipin IgM U/mL

2.0 (2.0-4.6)

2.0 (2.00-3.83)

0.621

Anti-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.


11
3.2.2.3. 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
TNFA (n=94)
IL6 (n=94)
IL10 (n=94)

Kidney lesion
[Median (quartile)]
have (n=86)

Are not (n=26)

9.76 (6.82-17.45)
11.05 (5.41-26.85)

6.53 (4.49-13.86)
17.61 (9.08-45.90)

P Value
0.050
0.221

4.93 (2.88-9.17)
5.01 (3.10-9.17)
0.738
TNFA 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
Hematological disorders

Cytokine
[Median (quartile)]
P Value
pg/mL
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)
0.149
IL10 (n=94)
4.90 (2.87-9.21)
7.08 (3.69-9.12)
0.514
There was a statistically significant difference (p = 0.024) in TNFA
levels between the two groups with haematological disorders and no
haematological 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
CNS lesions
Cytokine
[Median (quartile)]
p value
pg/mL
have (n=32)

Are not (n=80)
TNFA (n=94)
9.89 (7.58-17.87)
9.19 (6.14-17.04)
0.521
IL6 (n=94)
IL10 (n=94)

18.26 (9.81-34.46)

11.73 (4.83-27.84)

0.192

8.46 (4.69-11.58)

4.54 (2.37-8.51)

0.020


12
There was a statistically significant difference (p = 0.020) in IL10 levels
between the two groups with CNS involvements and no CNS involve.
3.3. Relation of autoimmune antibodies levels, complements,
immunoglobulins, cytokine and disease activity (SLEDAI)
3.3.1. Relation of autoimmune antibodies levels and SLEDAI
3.3.1.1. Relation of autoimmune antibodies levels and SLEDAI
Table 3.9. Relation of autoimmune antibodies levels with
SLEDAI score

SLEDAI
Antibodies

[Median (quartile)]
12-19 points
(n=38)

Anti-dsDNA

117.8 (40.7-240.0)

p value

 20 points (n=74)
240.0 (128.2-240.0)

0.005

Anti-Cardiolipin IgM

2.0 (2.0-4.63)

2.0 (2.0-3.8)

0.494

Anti-Cardiolipin IgG

3.15 (2.0-14.03)

8.0 (2.05-21.95)

0.187

7.5 (3.9-53.9)

7.0 (2.78-54.80)

0.712

Anti -Sm

Anti-dsDNA level were statistically significantly higher (p = 0.005) in
the very active group (SLDAI ≥ 20).
3.3.1.2. Correlation of anti-dsDNA levels and SLEDAI

r = 0.251
p = 0.007

Chart 3.1: Correlation between anti-dsDNA levels and disease activity
(SLEDAI)
Regression equation: SLEDAI = 0.023 x anti-dsDNA + 19.78


13
The level of anti-dsDNA associated with SLEDAI was proportional to
r = 0.251 and p = 0.007.
3.3.2. The average concentration of complement with SLEDAI
3.3.2.1. The average concentration of complements with SLEDAI
Table 3.10. Relation of complement levels with SLEDAI

score
Complement

SLEDAI
12-19 points (n=38)

 20 points
(n=74)

p value

C3 (n=112)

50.15 ± 30.62

34.01 ± 18.19

0.001

C4 (n=112)

12.74 ± 9.11

9.80 ± 6.97

0.059

mg/dL

Mean C3 concentrations were significantly lower in the SLE group and

were significantly associated with a SLEDAI score (p = 0.001).
3.3.2.2. Correlation between complement with SLEDAI
r = -0.267
p = 0.004

Chart 3.4: Correlation between serum levels of C3 and SLEDAI
Regression equation: SLEDAI = -0.093 x C3 + 27.37; C3 concentration
was negatively correlated with the SLEDAI score with
r = -0.093 and p = 0.004.
3.4. Results of pulse PM therapy in severe SLE
3.4.1. Changes of autoimmune antibodies levels


14
Table 3.11. Characteristics of changing anti-dsDNA levels

Anti-dsDNA
UI/mL
Increase ≥
50 UI
Median
(Quartiles)
min - max

after treatment

p value

Before
treatment

1W

4W

12 W

(n=80)
n%

(n=80)
n%

(n=80)
n%

(n=79)
n%

63 (78.8)

p0-1

p0-2

p0-3

43 (53.8) 31 (38.8) 23 (29.1) <0.001 <0.001 <0.001

240.0

(65.2240.0)

52.3
(20.322.6)

36.4
(16.480.4)

26.6
(14.354.3)

<0.001 <0.001 <0.001

3.29 –
0.85 –
0.79 –
240
240
137.6
The rate of anti-dsDNA (+) and anti-dsDNA levels decreased after
treatment for 1 week, 4 weeks and 12 weeks
3.4.2. Caracteristics of change C3, C4 and immunoglobulins levels
Table 3.12. Changes in C3, C4 and immunoglobulins
levels

Index
mg/dL

4.9 – 240

after treatment

P value

Before
treatment

1w

4w

12 w

(n=80)

(n=80)

(n=80)

(n=79)

79.54 ±
23.32

55.40 ±
22.19

p0-1

p0-2

p0-3

90.23 ±
20.27

<0.001

<0.00
1

<0.001

C3

41.67 ±
25.27

C4

10.95 ±
7.86

13.53 ±
7.48

18.84 ±
9.02

20.75 ±

10.10

<0.001

<0.00
1

<0.001

IgA

246.24 ±
103.30

206.32 ± 207.82 ±
83.60
80.01

225.18 ±
83.19

<0.001 0.001

0.091

IgE

545.17 ±
587.51

353.92 ± 366.26 ±
468.08
721.44

188.61 ±
214.94

0.001

0.052

<0.001

IgG

1170.72 ± 943.86 ± 944.76 ± 1007.95 ±
611.70
526.55
402.17
359.58

<0.001

<0.00
1

0.023

IgM

132.16 ±

0.005

0.173

0.786

104.75 ± 115.78 ±

129.52 ±


15
after treatment
P value
Before
treatment
101.27
59.87
61.79
53.23
Increased C3, C4 levels, decreased immunoglobulins levels
after treatment 1 week, 4 weeks and 12 weeks
3.4.3. Changes in cytokine levels
Table 3.13. Cytokine change before and after treatment

Index
mg/dL

Cytokine
pg/mL
Increased
TNFA
Median
Increased
IL6
Median
Increased
IL10
Median

Before
treatment

After treatment

n%

1 tuần- n %

4 tuần - n %

28 (42.4)

20 (32.8)

9 (15.8)

9.40 (6.4217.52)

8.26 (4.9214.72)

6.72 (4.788.77)

64 (97.0)

58 (95,1)

55 (96.5)

10.37 (4.6223.46)

10.47 (4.6120.01)

7.44 (3.3413.36)

56 (84.8)
4.89(3.058.44)

54 (88.5)
4.23 (2.69-6.81)

P value
p0-1

p0-2

0.052 <0.001

0.621

0.026

0.036

0.036

44 (77.2)
3.21 (2.127.16)

IL-10 was significantly reduced after 1 week of treatment (p =
0.036). Increases in TNFA, IL6, IL10 and TNFA, IL6, IL10 levels were
significantly reduced after 4 weeks of treatment


16
3.4.4. Evaluation of overall treatment response across the SLEDAI
Score
Table 3.14. Comparison of SLEDAI score before and after
treatment

SLEDAI

12 points

19

Before
treatm

ent

1w

4w

12 w

(n=80)
n%

(n=80)
n%

(n=80)
n%

(n=79)
n%

after treatment

P value

28 (35.0) 71 (88.8) 79 (98.8) 79 (100)

≥ 20 points 52 (65.0) 9 (11.3)

1 (1.3)

0

Mean

8.63
± 4.58

6.85
± 3.83

23.33
± 8.04

14,03
± 6.43

p0-1

p0-2

p0-3

<0,001

<0,001

<0,001

<0.001

<0.001

<0.001

(min -max)

12-49
2-42
0-29
0-18
SLEDAI score in both high and very active groups were
reduced by one week, after 4 weeks and after 12 weeks of treatment. The
mean score of SLEDAI was decreasing over time: before treatment was
23.33 ± 8.04, after 1 week it was reduced to 14.03 ± 6.43, after 4 weeks
8.63 ± 4.58 and after 12 weeks week 6.85 ± 3.83 points.
3.4.5. Evaluation of treatment response for lupus nephritis with
nephrotic syndrome
Table 3.15. Treatment response level of patients with
nephrotic syndrom
Response
after 1 w
After 4 w
After 12 w
P value
(n=47)
(n=47)
(n=47)
Completely

0

3 (6.4%)

9 (19.1%)

partian

15 (31.9%)

24 (51.1%)

33 (70.2%)

Not responding

32 (68.1%)

20 (42.6%)

5 (10.6%)

<0.001

After 1 week: no patients completely responsive, 31.9% partian
responsive, 68.1% not responsive. After 4 weeks: 6.4% completely
responsive, partian 51.1%, not responding 42.6%. After 12 weeks:
completely responsive 19.1%, partial 70.2%, not responding 10.6%


17

3.4.6. Evaluate the adverse effects of the therapy
Table 3.16. Adverse effects of therapy
Adverse effects of therapy
1w
4w
n%
n%
Severe infection
Pneumonia
Tuberculosis (lung)
Urinary infection

12 w
n%

10 (12.5%)
8
1
1

Epigastric pain

2 (2.5%)

dyslipidemia
Hyperglycemia

1(1.3%
)

Electrolyte disorders
Hypertension

2 (2.5%)

6
(7.5%)

1 (1.3%)

Atrial fibrillation
Cushing syndrome

12 (15%)

psychosis
Osteoporosis-head bone necrosis
The most noticeable adverse effects after 1 week of treatment: severe
infection 12.5%, epigastralgia 2.5%, hypertention 2.5%. Cushing
syndrome after 12 weeks of treatment is 15%.
CHAPTER 4- DISCUSSION
4.1. General characteristics of age and sex
The mean age of the study group was 25.65 ± 7.71, with the
prevalence of the disease ranging from 20 to 29 years old to 45.5%.
Aging age is also consistent with many other studies in and outside the
country.
4.2. Characteristics of immune disorders in severely SLE, associated
with some immunological indices with organ damage and with the
SLEDAI score.

18
4.2.1. Characteristics of immune disorders in severe SLE
4.2.1.1. Characteristics of autoimmune antibodies
The autoimmune antibodies in the study group showed that
ANA positive was 98.2%, anti-dsDNA 79.5%, anti-Sm 42.7%, antiCardiolipin IgM 6.8%, anti-Cardiolipin IgG 27.2%, anti-SSA 51%, antiSSB 13%. According to study Pham Van Thuc, the rate of ANA (+)
66.76%, anti-dsDNA (+) 60.92%, study of Hoang Tram Anh, the rate of
anti-dsDNA (+) 60.5%. Al-Shamahy's study showed that ANA (+)
95.3%, anti-dsDNA (+) 59.7%, anti-Sm (+) 27.5%. Our study had a
number of autoantibodies similar to those found in Cervera, which
showed ANA (+) 96%, anti-dsDNA (+) 78%, anti-Sm (+) 10%, anti
Cardiolipin IgM (+) 13%, anti-Cardiolipin IgG (+) 24%, anti-SSA (+)
25%, anti-SSB (+) 19%.
Autoimmune antibodies in severe SLE are diverse and
abundant. The rate of autoimmune antibodies may vary according to
study. Antibodies with a high positive rate such as ANA are very
valuable in the diagnosis of SLE. In addition, ANA has a positive rate
for almost all SLE patients, it is also very valuable in the diagnosis
exclusion of SLE when ANA negative.
4.2.1.2. Characteristics of complements levels and immunoglobulins
levels
Results showed that most patients had a decrease in C3 (94.6%)
and C4 (63.4%). This study was consistent with many studies on C3, C4
levels in SLE. Some studies have shown that C3 and C4 levels are
associated with disease activity and are one of the indicators that can be
used to monitor the disease status and assess the response to treatment.
About the immunoglobulins in this study we found that 80% had
increased IgE. According to a study by Liphaus et al., IgE was found to
increase in 45% of patients with lupus.
4.2.1.3. Characteristics of cytokine levels (TNFA, IL6, IL10)

Results showed that TNFA levels in this study were 40.4%,
almost all patients showed increased IL6 levels of 95.7% and IL10 levels
of 85.1% . Cytokines play an important role in the pathogenesis of SLE,
and some studies have shown a correlation between cytokine levels and
target organ damage, which is important in the pathogenesis of SLE.
Postal's study showed that elevated TNFA levels in active SLE
compared with controls, and Maury's study showed that there was an
increase or no increase in TNFA in SLE patients. Our study showed that
the TNFA increase was lower than that of Studnicka, in which 85%


19
TNFA was increased, and TNFA levels were associated with active SLE.
The IL6, IL10 are two cytokines that play an important role in the
pathogenesis of SLE. According to Llorente's study, IL10 is increase in
active SLE and plays an important role in the pathogenesis of SLE.
4.2.2. Analysis of the association between autoimmune antibodies,
complements levels, cytokine levels and target organ damage.
4.2.2.1. Autoimmune antibodies and target organ demage
We analyzed the levels of some autoimmune antibodies with
target organ damage by evaluating group of arthritis and no arthritis,
hematologic disorders and no haemorrhagic disorders, no kidney lesion
and no kidney lesion and CNS involvement and no CNS involvement to
find correlation between autoimmune antibody and target organ damage
The role of anti-dsDNA is related to the activity of the disease,
some studies have also shown that the anti-dsDNA increases before the
onset of the disease. Alba's study shows that anti-dsDNA and anti-Sm
levels may be associated with lupus nephritis. The results of our study
found that mean of anti-dsDNA levels in the kidney lesion group were
higher than those without kidney lesion but not statistically significant,

and mean of anti-Sm levels differed these two groups (p = 0.021) and
this is also fit with the Arroyo M study; suggesting that anti-Sm may be
related in specific organ damage such as kidney, central nervous system,
hematological and vascular inflammation in SLE.
4.2.2.2. Complements levels, immunoglobulins levels and target
organ damage.
We found that serum IgG levels were associated with arthritis,
haematological disorders and kidney lesion in SLE. This finding is
consistent with studies by Cass et al., Who showed that the levels of IgG
were related to the active disease, and anemia in SLE. We also found
that IgG levels were associated with renal impairment, which is
consistent with study of Yap et al; found that 26% of nephritis lupus
have reduction IgG levels and associated with proteinuria status in active
SLE. Our study are consistent with the findings of Ktona et al; regarding
the association of C3, C4 reduction with thrombocytopenia and
leucopenia in SLE.
C3, C4 levels and immuniglobuoins disorders in SLE may be
associated with some target organ damage, reduced IgG levels
associated with kidney lesion and some differences lesions in active
SLE, low C3, C4 levels may be associated with haematological disorders
in SLE.


20
4.2.2.3. Cytokines levels with target organ damage
We found that TNFA levels may be associated with kidney
lesion and haematological disorders (with p = 0.050 and p = 0.024),
which is consistent with Herrera E's study of the role of TNFA in
nephritis lupus, and also similar with Postal's review of the role of TNFA
with organ damage in the flare of SLE. In this study we also found

differences in IL10 levels between the CNS involvement group and the
non-CNS involvement group and this is consistent with McCarthy's
study of the role of some cytokines in organ damage in SLE.
In this study, we did not find any difference in IL6 levels with
organ-specific lesions. Research by Zhihua Yin on the study of eight
cytokines including TNFA, IL6, and IL10 also showed that the role of
IL10 is related to disease activity, however, relared with specific organ
lesions is unclear.
4.2.3. Relation of autoimmune antibodies levels, complements, and
disease activity (SLEDAI)
4.2.3.1. Relation of autoimmune antibodies levels and SLEDAI
The relationship between the level of antibodies and the severity
of the disease was found to be related to the level of anti-dsDNA and
activity disease and statistically significant and also to other studies.
According to the results of the study, we found that the levels of other
antibodies not related to active disease. In addition to anti-dsDNA, CRP,
ferritin, C3, C4, some cytokines, B-cell markers, anti-nucleosomes, and
anti-C1q are biological indicators that are related with active SLE.
Results showed that anti-dsDNA was correlated with disease
activity with coefficient r = 0.251, p = 0.007. This finding is consistent
with many studies on the role of anti-dsDNA in the evaluation of SLE
activity. Thus, anti-dsDNA is not only a diagnostic value but also a
measure of the level of active SLE.
4.2.3.2. The relationship between the complements levels and SLEDAI
In relation to the concentration and activity of the disease, we
found that C3 levels were statistically related to the activity of the
disease. According to some studies, the complements levels are related
to active disease and this is consistent with our results.
The correlation between C3 and SLEDAI showed that the C3
level was related to the activity of SLE with correlation coefficient of C3

with SLEDAI r = -0.267, p = 0.004. This finding is consistent with other
studies of the role of C3 in the assessment of SLE activity


21
4.3. Results of pulse PM therapy in severe SLE
4.3.1. Changes of anti-dsDNA levels
The rate of patients with an anti-dsDNA antibody titre of ≥ 50
UI decreased before and after treatment and decreases over time, and the
anti-dsDNA level is also decreases with time after pulse MP. Thus, the
anti-dsDNA level decreases with the degree of response to treatment and
is also consistent with other studies evaluating the role of anti-dsDNA in
the assessment of disease activity and treatment monitoring. Nghiên cứu
của Narayanan cho thấy rằng anti-dsDNA có liên quan chặc chẽ với mức
độ hoạt động của bệnh. Narayanan's study shows that anti-dsDNA is
related to the degree of activity of the disease. Arbuckle's study shows
that elevated anti-dsDNA also has a prognostic value for SLE before
clinical manifestations. According to a review by Reveille, anti-dsDNA
levels have prognostic value, target organ damage, and assessment of
treatment response.
Anti-dsDNA levels decreased after pulse MP therapy at weeks
1, 4, and 12 weeks. Anti-dsDNA levels reduced have the relation to
responsive treatment with this therapy. Thus, the pre-treatment and posttreatment anti-dsDNA levels are useful in assessing the response to
treatment, in addition to monitoring the anti-dsDNA level as well as the
prognostic value of the disease.
4.3.2. Caracteristics of change C3, C4 and immunoglobulins levels
Changes in C3, C4 levels were statistically significant after 1
week, 4 weeks and 12 weeks with pulse MP. Narayaran's study shows
that C3, C4 levels are valuable in assessing SLE activity and are
significantly associated with SLEDAI.

Evaluation of changes in IgA, IgE, IgG and IgM levels was
found to be statistically significant after 1 week of pulse MP. According
to Eyanson's assessment of the effect of pulse MP in patients without
kidney lesion, also reported to reduce IgG after pulse MP therapy, but
according to a review of Kurki's study the effect on immunoglobulins
with pulse MP did not always indicate a decrease in immunoglobuins
levels after pulse MP therapy.
Pulsed MP therapy improves C3, C4 and reduces some of the
immunoglobulins observed at weeks 1, 4 and 12 weeks after treatment in
this study. Monitoring of C3, C4, immunoglobulins and SLEDAI score
was used to assess treatment response and prognosis.
4.3.3. Changes in cytokine levels


22
IL-10 was significantly reduced after 1 week of treatment (p =
0.036). Increases in TNFA, IL6, IL10 and TNFA, IL6, IL10 levels were
statistically significantly decreased after 4 weeks of pulse MP. This
result is consistent with the mechanism of action of pulse MP on
reduction of cytokine production and also in accordance with Bai's
study, the TNFA level decreased after pulse MP.
Thus, TNFA, IL6 and IL10 plays an important role in the
mechanism of SLE, pulse MP therapy reduces the cytokines levels at
observation time after 1 week, after 4 weeks.
4.3.4. Evaluation of overall treatment response across the SLEDAI
score
The average SLEDAI score was 23.33 (SLEDAI score ≥ 20
points is 65%). The SLEDAI score was statistically significantly reduced
after 1 week, 4 weeks and 12 weeks after pulse MP therapy; Specifically,
SLEDAI scores an average of 14.03 points after 1 week, 8.63 points

after 4 weeks (SLEDAI ≥ 20 points is 1.3%), and after 12 weeks
SLEDAI average score is 6.85 points (no patients with SLEDAI score ≥
20 points). This study is also consistent with Pham Huy Thong's study of
the effect of pulse MP in nephritis lupus.
4.3.5. Evaluation of treatment response for lupus nephritis with
nephrotic syndrome
In 80 patients of pulse MP therapy in our study have 47 patients
with diagnosis of nephrotic syndrome (58.75%). We evaluated the
effectiveness of pulse MP therapy for this group, we performed
subgroup analyzes of several characteristics and evaluated the response
of pulse MP therapy on this group.
We found that the response rate after pulse MP therapy was as
follows: after 4 week response completely was 6.4%, after 12 weeks it
was 19.1%, the response partial was 51.1% 4 weeks and after 12 weeks
were 70.2%. The rate of patients who did not respond after 4 weeks was
42.6% and after 12 weeks it was 10.6%.
Results of Pham Huy Thong' sdudy showed that after 1 month
of treatment, the complete response was 14.28%, partially response was
50%, not response was 35.72%; After 3 months of treatment: The
complete response was 32.14%, partially response was 35.71%, not
response was 32.1%. Thus pulse MP therapy was quite satisfactory
results for lupus nephritis with syndrome nephrotic.
4.3.9. Evaluate the adverse effects of the pulse MP therapy


23
The adverse effects of pulse MP therapy were observed in the
12 weeks most notable severe infection was 12.5%, especially in the first
week after treatment.
CONCLUSIONS

Study to characteristics of immune disorders in 112 severe SLE and
follow-up treatment for 80 patients with pulse MP we had some
conclusions as follows:
1. Characteristics of immune disorders in severely SLE, associated
with some immunological indices with organ damage and
with the SLEDAI score.
1.1. Characteristics of immune disorders
The ANA (+) ratio was 98.2%, anti-dsDNA (+) 79.5%, anti-Sm (+)
42.7%, anti- Cardiolipine IgM (+) 6.8%, anti-Cardiolipine IgG (+) 51%,
anti-Ro (+) 51%, anti-La (+) 13%. The C3 decrease was 94.6%, C4
63.4%, IgA 8.3%, IgE 80%, IgG 25.7%, and IgM 9.2%. TNFA increased
40.4%, IL6 increased 95.7%, IL10 increased 85.1%.
1.2. Relate some of the immunity indicators and organ damage
Antibody levels of anti-dsDNA and anti-Cardiolipin IgG have
been associated with haematological disorders, anti-cardiolipin IgM
level have been associated with kidney lesion. C3, C4 levels are related
to hematologic disorders. TNFA levels may be associated with kidney
lesion and hematologic disorders, IL10 levels have been associated with
CNS involvement.
1.3. Relate some of the immune indicators to the activity of the disease
(SLEDAI)
Anti-dsDNA, C3 levels are associated with the SLEDAI score
2. Results of pulse PM therapy in severe SLE
2.1. Changes of autoimmune antibodies levels, complements levels,
immunoglobulins levels, cytokine levels
Anti-dsDNA levels decrease after pulse MP therapy. Increased
levels of C3, C4, decreased the concentration of some immunoglobulins
after treatment. TNFA, IL6, IL10 levels decreased after pulse MP
therapy.
2.2. Effectively improve SLEDAI score