Intravenous pulse methylprednisolone in severe systemic lupus erythematosus

JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017

INTRAVENOUS PULSE METHYLPREDNISOLONE IN
SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS
Huynh Van Khoa*; Le Anh Thu*; Le Thu Ha**
SUMMARY
Objectives: To evaluate the effective and the safety of pulse methylprednisolone (MP) in
severe systemic lupus erythematosus (SLE) flares. Subjects and methods: An interventive and
comparative study was carried out on 80 patients with SLE flares. Results: We followed
80 patients with severe lupus flare who were treated with pulse MP in 12 weeks. The patients
were assessed before the treatment (T0), 1 week after the treatment (T1), 4 weeks after the
treatment (T2) and 12 weeks after the treatment (T3). The anti-dsDNA titer significantly
decreased after the treatment (163.91 ± 92.67 at T0, 82.90 ± 75.61 at T1, 54.22 ± 50.66 at T2
and 35.88 ± 27.68 at T3. The SLEDAI score also significantly improved with the mean decrease
(23.33 at T0, 14.03 at T1, 8.63 at T2 and 6.85 at T3). The rate of patients with SLEDAI above
20 decreased after the treatment (65% at T0, 11.3% at T1, 1.3% at T2, and 0% at T3). As for
47 patients with nephrotic syndrome, at T1, no patients had complete response rate, partial
response were seen in 31.9% and no response 68.1%, at T2, 6.4%; 51.1% and 42.6%,
respectively, at T3, 19.1%; 70.2% and 10.6%, respectively. The infection was seen in 12.5% of
those patients, mostly in the first week after the pulse MP. Conclusion: Pulse MP seemed to be
effective in the SLE patients on severe flares. The most common adverse effect of this therapy
is the infection, especially in the first week after the pulse.
* Keywords: Severe systemic lupus erythematosus; Nephrotic syndrome; Pulse therapy.

INTRODUCTION
Lupus is a systemic autoimmune disease
that occurs when your body's immune
system attacks tissues and organs.
Inflammation caused by lupus can affect
many different body systems, including
joints, skin, kidneys, blood cells, brain,

heart and lungs. Lupus can be difficult to
diagnose because its signs and symptoms
often mimic those of other ailments. The
most distinctive sign of lupus, a facial rash
that resembles the wings of a butterfly
unfolding across both cheeks occurs in

many but not all cases of lupus. Severe
organ damage is one of the most common
causes of mortality in systemic lupus
erythematosus, directly or indirectly [10].
Intravenous high dose of methylprednisolone
(pulse therapy) given as monotherapy or in
combination with other immunosuppressive
agents has been used in life threatening
flares of SLE, and has been shown to be
effective by many trials [1, 2, 8, 9]. This
study aimed to: Evaluate the effectiveness
and the safety of pulse MP therapy in
patients with severe flares of SLE.

* Choray Hospital
** Central Military Hospital 108
Corresponding author: Huynh Van Khoa ()
Date received: 30/09/2017
Date accepted: 22/11/2017

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JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017
SUBJECTS AND METHODS
1. Subjects.
This study was carried out at
Rheumatology Department, Choray Hospital
from May 2011 to December 2015. We
enrolled 80 patients having SLE according
to American College of Rheumatology
criteria in 1997 with severe flare (SLEDAI
≥ 12 and at least 1 severe organ damage) [6].
They were given pulse methylprednisolone
(pulse MP) 1 gram per day in 3 consecutive
days, and were periodically assessed the
clinical, laboratory test and SLEDAI indexes
before treatment (T0), 1 week (T1), 4 weeks
(T2) and 12 weeks (T3) after the pulse MP
to evaluate the treatment effectiveness.
- Severe organ damages were defined
as lupus nephritis with nephrotic syndrome,
severe hemolytic anemia, alveolar hemorrhage
and myocarditis.

- The effective outcomes were the
improvement of anti-dsDNA titer and SLEDAI.
- As for the treatment of nephrotic
syndrome, based on KDIGO 2012 (Kidney
Disease Improving Global Outcomes)
criteria [7], the response was defined as:
+ Complete response: Proteinuria is
lower than 0.5 g per day, albuminemia at

least 3 g/dL; GFR > 60 mL/min or GFR
increase more than 50% after the treatment,
no urinary blood and cast.
+ Partial response: Proteinuria decreases
more than 50% after treatment, albuminemia
< 3 g/dL and GFR improvement > 50%
after treatment.
+ No response: Proteinuria > 3 g per day,
proteinuria decrease < 50% after treatment
and GFR decrease < 20% after treatment.
2. Methods.
Interventive trial with compare pre- and
post-treatment.

RESULTS AND DISCUSSION
1. Treatment response: anti-dsDNA outcome.
Table 1: Change of anti-dsDNA.
AntidsDNA
titer
≥ 50 UI/mL
Mean

After treatment

p value

Before
treatment

T1

T2

T3

(n = 80), n %

(n = 80), n %

(n = 80), n %

(n = 79), n %

63 (78.8)

43 (53.8)

31 (38.8)

23 (29.1)

p0-1

163.91 ± 92.67 82.90 ± 75.61 54.22 ± 50.06 35.88 ± 27.68

p0-2

p0-3

< 0.001

< 0.001 < 0.001

< 0.001

< 0.001 < 0.001

Positive anti-dsDNA test rate and mean anti-dsDNA titer decreased 1 week, 4 week
and 12 weeks after treatment. The frequency of patients with positive anti-dsDNA
(≥ 50 IU/mL) reduces post-treatment in comparison with pre-treatment, and trends to
decrease with time. The same observation was seen with anti-dsDNA level. Anti-dsDNA
level was shown to correlate with disease activity in SLE, and was a tool in monitoring
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JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017
the treatment effect in other previous studies [3]. Some authors proved that anti-dsDNA
could not only used in disease activity assessment but also in monitoring the treatment
response and has a tight correlation with SLEDAI. Anti-dsDNA titer decreased 1 week,
4 weeks and 12 weeks after pulse MP. Anti-dsDNA titer decrease reflected the
response of the patients to the treatment.
2. Response rate: SLEDAI outcome.
Table 2: SLEDAI change pre- and post-treatment.
Post-treatment

p value

Pre-treatment
1 week

4 weeks

12 weeks

(n = 80)
n%

(n = 80)
n%

(n = 80)
n%

(n = 79)
n%

12 - 19

28 (35.0)

71 (88.8)

79 (98.8)

79 (100)

≥ 20

52 (65.0)

9 (11.3)

1 (1.3)

0

Mean

23.33 ± 8.04

14.03 ± 6.43

8.63 ± 4.58

6.85 ± 3.83

12 - 49

2 - 42

0 - 29

0 - 18

SLEDAI

(Min-max)

p0-1

p0-2

p0-3

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

< 0.001

High and very high disease activity rates decreased 1 week, 4 weeks and 12 weeks
after treatment. The mean of SLEDAI decrease with time: 23.33 ± 8.04 pretreatment,
14.03 ± 6.43 one week, 6.63 ± 4.58 four weeks and 6.85 ± 3.83 twelve weeks after
treatment. In table 2 showed that the mean SLEDAI before treatment was 23.33
(SLEDAI ≥ 20 occupied 65% of the total population), and the SLEDAI significantly
decrease 1 week, 4 weeks and 12 weeks after pulse MP. In detail, the mean SLEDAI
after 4 weeks was 8.63 (1.3% of patients having SLEDAI ≥ 20), and 4 weeks 6.85
(no patient with SELDAI ≥ 20). In a trial on lupus nephritic patients, Pham Huy Thong
proved that pulse MP had favorable effects on SLEDAI outcome after 1 month and 3
months of follow-up [2]. According to Basda's study, the effect of pulse MP at different
doses showed a significant reduction in SLEDAI after 6 months of follow-up [4]. Our study
showed that the pulse MP had a rapid effectiveness, only after 1 week, and the effectiveness
was the highest at 4 weeks after treatment.
3. Nephrotic syndrome group.

Of 80 patients treated with pulse MP, there were 47 ones fulfilled nephrotic
syndrome criteria.
Table 3: Response classification of patients having nephrotic syndrome (n = 47).
Response

After 1 week, n (%)

4 weeks, n (%)

12 weeks, n (%)

0

3 (6.4)

9 (19.1)

Partial

15 (31.9)

24 (51.1)

33 (70.2)

No response

32 (68.1)

20 (42.6)

5 (10.6)

Complete

p

< 0.001

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JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017
After 1 week, there was no patient with
complete response, 31.9% of them
achieved partial response and 68.1% no
response. These rates at 4 weeks were
respectively 6.4%; 51.1% and 42.6%;
after 12 weeks 19.1%; 70.2% and 10.6%,
respectively. Pham Huy Thong’s study
showed that after 1 month of treatment,
14.28% of the patients achieved complete
response, 50% partial response and 35.72%
non-response; after 3 months, 32.14%
had complete response, 35.71% partial
response and 32.1% non-response [2].
The complete response rate after 3 months
of treatment in our study was lower than
in Pham Huy Thong’s study, but the partial
response was higher and non-response in

our study was lower than in his. This
discrepancy could be explained by the
differences of population Pham Huy Thong’s
study characteristics between 2 studies.
We included only those with nephrotic
syndrome, while Pham Huy Thong’s study
enrolled all patients with prolonged renal
insufficiency more than 3 months, and
proteinuria more than 2 g per day in more
than 2 months [2]. After 12 weeks of
follow-up, we concluded that the response
rate of SLE patients with nephrotic syndrome
was 89.3% (of which complete response
19.1% and partial response 70.2%).
According to Kimberly’s study, pulse MP
was considered to be effective in improving
renal function in 12/34 (35.29%) of patients
after 2 months [9]. So, pulse MP has a
good response rate in the renal injury
patients with nephrotic syndrome.
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4. Adverse events of pulse MP (n = 80).
Table 4: Adverse events of pulse MP
(n = 80).
Adverse events
Severe infection

1 week
n (%)

4
weeks

12
weeks

10 (12.5%)
8

Pneumonia tuberculosis
(lung) urinary tract
infection
Epigastric pain

1
1
2 (2.5%)

Hyperglycemia

1 (1.3%)

Disorders of electrolytes
Hypertension
Cushing syndrome

2 (2.5%)

6 (7.5%) 1 (1.3%)

12 (15%)

The most important adverse events
after pulse MP: infection 12.5%, epigastric
pain 2.5%, hypertension 2.5%. Cushing
syndrome was seen in 15% of patients
after treatment. Among the adverse events
observed in 12 weeks of follow-up, infection
was the most remarkable. Our study showed
10 severely infected patients (12.5%),
especially in the first week after treatment.
Pneumonia was quite common, among
those with pneumonia, there was one with
severe pneumonia who was fatally ill
and was discharged as the family’s will.
The other manifestation less frequent
were epigastric pain (2.5%), hypertension
(2.5%). Cushing syndrome was common
with 15% of patients after 12 weeks,
though this could be due to the prolonged
corticosteroid rather than to the pulse MP.
In Pham Huy Thong’s study, infection was
the most common adverse events at the
rate of 16.6% [2]. This was also seen in
other studies on pulse MP. Boumpas
studying pulse MP in 25 SLE patients
showed that 3 cases infected with Herpes


JOURNAL OF MILITARY PHARMACO-MEDICINE N09-2017

zoster, 3 cases of osteonecrosis, 6 cases
of cataract [5]. Zonana’s study on adverse
effects of corticosteroid in lupus showed
that the accumulative dose of corticosteroid
had a relationship with the increased
osteoporotive fracture, stroke, cataract,
avascular osteonecrosis, and mellitus
diabetes risk. Pulse MP caused only a slight
increase in osteoporotic fracture risk, but
not statistically significant.
CONCLUSION
Our study showed that pulse MP therapy
was effective in SLE flare by significantly
lowering the anti ds-DNA titer and SLEDAI
score. In the nephrotic syndrome group,
we noticed that after 1 week, there was
no patient achieving complete response,
31.9% partial response and 68.1% no
response; after 4 weeks, the complete
response rate was 6.4%, partial response
51.1% and non-response 42.6%; after
12 weeks, 19.1% had complete response,
70.2% partial response and 10.6% nonresponse. Infection occurred in 12.5% of
patients on pulse MP, especially in the
first week after the treatment.
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