SEVERE LUPUS: CHALLENGE IN RECOGNIZING DIAGNOSE

AND LIFE SAVING

*Ni Putu Yunik Novayanti, Ketut Dewi Kumara Wati
Department of Child Health, Medical School of Udayana University,Sanglah Hospital

Background : A wide range in clinical presentation of children systemic lupus

eritematosus (SLE) raising difficulty in building diagnosis. Delay diagnosis lead higher
morbidity and mortality. Moreover children SLE has more agressive and severe
manifestation than adult, potentially met multiple organ dysfuntion and life threatening
condition during managing the diasease.
Objective : To shows how recognizing the case as a chronic disease, and managing
severe condition related to SLE
Case : A boy, 11 years-old, present with prolonged febris, oral ulcer, seizure, edema
anasarca, severe hypoalbumin (albumin 1,8 g/dL), pleural and pericardial effusion,
transaminitis, hepatomegaly, acute kidney injury, pancytopenia, hemolytic anemia (Hgb
3,5 mg/dL) with positive 4 coomb test, hypertension grade II, electrolyte imbalance. Low
C3 complement (22 g/dL) was noted. SLE established on 7th day of hospitalization.
Methylprednisolon pulse intravenous was ruled out at dose 30 mg/kg daily for 3 day
continued with 2 mg/kg/day. Unfortunatly, the 8th of hospitalization the GFR falls to 49.1
ml/min. Urgent hemodialysis and CYD need, but can we start CYD in severe anemia ?
Can we add more fluid for hydration before CYD despite anasarca edema & hypocalemia.
Life saving consideration. CYD must be started. Transfusion with premedication,
conventional hydration with titrating furosemid prepared. Close monitoring for
pulmonary-cardiac-renal-cerebral function, electrolyte level was done. Pulse CYD was
given at dose of 500 mg than repeated every 2 week. Once the CYD started GFR incresed
gradually, anemia resolved, serositis resolved, liver function test improved. No side effect
cystitis hemoragic nor neutropenia.

Keyword : severe lupus, diagnosis, multiorgan disfuction

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INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune

disease characterized by periods of increased disease activity caused by inflammation of

blood vessels and connective tissue.1 As it is chronic and multisystem, the clinical

manifestation variation and it’s capability mimic other diseases presentation lead the

difficulty to diagnose.

Epidemiology studies show SLE are commonly female. The female : male ratio

is 3 : 1 before puberty, and increased after puberty to 9 : 1.1. When it is affect male patient

become more difficult to recognized hence patient can be situated in high risk worst

outcome or morbidities. This high risk should be understand in children population as in

general children with lupus has severe presentation than adult SLE. Most data describe

that children SLE is more aggresive disease, having higher prevalence of renal,

hematologic, central nervous system involvement at the time diagnosis compared to

adults with SLE.2,3 Lupus nephritis is the most serious form and may lead life threatening

condition to death. Mortality was higher in children SLE than adult SLE, 9% and 7%

respectively.4 Mortality may occur during diagnosis or treatment.

Cyclophospamide known as a strong immunosupresive agent, widely used in

malignacy and immunological disease. Although rheumatology management pediatric

SLE 2016, recommended cyclophospamide as primarily used for the management of

severe SLE moreover evidence showed satisfy disease response but the

proceduremanagement in life treatening, multiorgan disfunction were rarely reported.

Mainly problem conducting cyclophospamide treatment would be araise because of its

toxic effects. Needs a lot of consideration facing contraindicative condition while

cyclophospamide must ruled.

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 Here are report a case of SLE patient in 11 years old male to show how recognizing

the case as a chronic disease, and managing severe condition related to SLE

CASE

An eleven years old boy was reffered to Sanglah hospital at June 27th 2015 with

suspect sepsis and acute kidney injury. He was complain of swollen and pale 4 days

before admitted to the hospital, accompanied by decreasing in urinary frequency. He

didn’t pass urine for over 12 hour before admited, at admision the urinary production

about 20 ml and colour is dark, jaundice arised a day earlier. He has a history 2 month of

lost of appetite and weight, fatique, recurrent skin infection and followed by 6 week of

febris, intermiten. The last fever occured 4 day before admitted. There was no nausea and

vomiting or other abdominal discomfort complain except fluidy stools twice a day

without blood and mucus at least 3 day before admited. No history of traveling to

endemic malaria places, nor sore throath, no other drugs had consums other than doctors

receipt. A month ago he got medication from Dermatologist according to skin infection

but did not overcome. He also comes to Internist twice because febris and his lose of

appetite as well as weight lose and he got antihelmintes and vitamins. Since pediatrician

he was blood tested than reffered to Sanjiwani having rehidration than toward Sanglah

hospital.

He was born aterm vigorously and via spontaneus vaginal delivery at a local

midwife, with birth weight of 3500 grams. There were no data of his birth height, head

circumference and thoracic circumference. No feasible abnormality was found. His

mother was 33 year old (G4P3003). During her pregnancy, there was no history of fever,

rash other serious disease, or taking medication. She had antenatal care regularly.

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 The immunization history was complete according to the recommended

immunization plan by goverment. His growth and development were normal. He was

fully breastfed for 6 month of age and began eat milk porridge upon 6 months old. He

was the youngest child in his family. None of his family member had the same complaint.

The boy and his family lived in a permanent house. The father worked as labor. He was

loved and cared by his parents and siblings.

The physical examination revealed respiratory rates 20 times/minute, saturation

was normal by pulseoxymetry, pulse rate 92 times/minute, blood pressure 150/90 mmHg,

patient look pale, ikterus, the mouth mucosal was dry and fisuras at both angle,

auskultation of heart revealed normal. Lungs remark rhales without retraction, edema

anasarca, ascites, liver enlargment 2 cm below arcus costae, coin lesion of extremity that

we sought as a dry impetigo lesion, and nail discoloration. No regional lymphonode

enlargement, nutritional status were good. Patient did not toxic, and he was quite alert.

Laboratory studies (Table 1) at the time of admission shows anemia (7,6 g/dL),

leukopenia (2,52x10-3 k/uL),thrombocytopenia (74 x 10-3 k/uL), the differential leucocyte

count showed lymphopenia and neutrophilia, elevation of aspartate aminotransferase

(540,9 ) and alanin aminotransferase (119,2), kolestasis (total bilirubin 6,9; direct

bilirubin 6.52), hypoalbumin (1,78 g/dL), homeostasis profile was normal, hyponatremia

(102 mmol/L), hypocalsemia (6,3 mmol/L). C-reaktive protein (2,4), urinalysis shows

proteinuria (25mg/dL), hematuria (+4), and bilirubinuria (+3). Chest x-ray was normal

(Figure 1.1). Renal function test unrevealed. The preliminary diagnose was hepatorenal

syndrome et causa suspect cholestatic type of hepatitis, acute kidney injury failure state

et causa suspect nephritic syndrome post streptococcal infection, hypertensi grade II and

pansitopenia. He was cosulted to nephrology and hepatology division and treated with

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furosemide 10 mg intravena and captopril 12,5 mg twice a day, albumin transfusion,

sodium correction, and trace to other nephritic caused posibility (C3, ANA test, anti-Ds

DNA, C4) leptospirosis posibility, urinary infection and sign of cronic renal disease.

From hepatology found there was an acute liver injury et causa hepatitis autoimune dd/

viral hepatitis dd/ drug induced. The treatment was vitamin K injection 2 mg every 2

week and ursodeoxycholate acid. Additional test support was consider to investigate the

causa and other morbidity.

During nursing (7 hours from admision) the patient exhibite joint pain at his left knee

accompanied by fever (38 ⁰C). The blood pressure turn to normal (110/70 mmHg) without

consumming antihypertension, diuresis was normal. Renal function test revealed normal

(GFR 108). Urinalysis shows hematuria (+4) without proteinuria, leucocyte

sedimentation within normal limit. The urine colour turn yellow and there seems like

improvement in renal function

At the second day (June 28th, 2015) he was suffered from seizure, the seizure was

general tonic ,upward rotation of both eye balls, occurred approximately one minute than

stopped by its own. After the seizure, patient is unconscious, his body temperature

increased (39 ⁰C). No hypertension, blood sugar was normal. The patient treating with

anti convulsan. Blood gas analysis revealed respiratory alkalosis (PH 7,41; pO2 120

mmHg; pCO2 21 mmHg; HCO3 13,3 mmol/L; BEecf -11,3; SO2 99%). Electrolyte

evaluation shows hyponatremia still persist (112 mmol/L) although we had doing

correction twice, also hypocalsemia (8,2 mmol/L), electrolyte urine shows normal. A few

hours later the patient complained of consciousness began decline and fall in a state of

shock. He was treated with fluid resuscitation and diagnose as shock hypovolemia et

causa suspect sepsis (et causa leptospirosis dd/ hepatitis), encephalopathy metabolic. He

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treated with cefoperazone sulbactam,anticonvulsant, albumin corection was continue,

calsium and sodium corection was done. Nutritional management improved to support

micro and macronutrients patient requirement. Pasient consulted to tropical disease

division treated together. Patient plant to get intensive care. Other test shows anti

leptospirosis were negatif, anti-HAV, anti-HCV, HbsAg were negative respectively.

ASTO normal (200), Procalsitonin increased (4,13), blood smear shows : erythrocyte

hypocromic microcytic anisopoikilositosis (fragmentosit (+), pencil cell (+),burr cell (+),

macrocytic (+)); leucocyte : the number decrease, blast (-); thrombocyte : the number

decrease, no clumping. Conclucion : anemia hypocromic microcytic anisopoikilositosis,

leukopenia,thrombocytopenia.

The day fourth (30th June 2015), pasient got second seizure, same type occured

about 2 minutes. Neurologic status did not improved (Gasglow Coma Scale 12/15).

Hemodynamic stable, respiratory rate was increased 30 times per minute, body

temperature 39 ⁰C. Edema was expanded, lever palpable 4 cm (increased) below arcus

costa. Albumin still low (1,9 g/dL) after correction, protein urine (Esbaach) revealed

normal, sodium increased at 125 mmol/L. Abdomen ultrasonography shows there was no

bilier obstruction, bilateral pyelonephritis (NS ?), bilateral pleural effusion, ascites. The

second chest-x ray shows bilateral pleural effusion supect organization process. Urine

culture growth staphylococcus aureus with colony count 100.000 colony/ml which was

sensitive to gentamicin or trimethoprim sulfamethoxazole. Urinary track infection was

establised, cefoperazone was continued, gentamicin was added.

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Table 1. Laboratory finding before and after cyclophosphamide (CYD)
Laboratory At Admission 9 days After 5 days After
Parameter (27th June ) CYD I (20th June) CYD II (30th June) Discharge
WBC (x103 K/µL) 2,02 7,67 3,46 9,1
Neutrofil (x 103 K/µL) 1,4 7,01 2,6 7,04
Lymphosite (x 103 K/µL) 0,36 0,4 0,45
Haemoglobin ( mg/dL) 6,8 5,9 9 9,14
Thrombocyte (x 103 K/µL) 74 92 118 151
MCV 80,6 - - -
MCH 25,5 - - -
Direct bilirubine 6,52 0,58 - -
Total bilirubine 6,9 1,22 - -
SGOT 540,9 23 - -
SGPT 119,2 13 - -
Gamma GT 497 46 - -
Total protein 4,64 4,7 - -
Albumin 1,78 2,4 - -
Blood Ureum 35 65,89 25,23 22
Creatinin serum 0,75 1 0,5 0,37
Sodium 103 131 135 141
Kalium 5,09 3,64 6,59 4,5
Cloride 81,8 94 106,7 109,3
Calcium 6,36 6,99 7,82 8,29

The day sixth (July 2th 2015) we found patient with anemia hemolytic.

Haemoglobin consentration decreased (Hb 5,4 g/dL; MCV 78 pg; MCH 26,5 pg). Direct

coomb test positif 4 which was known after pack red cell (PRC) product transfusion was

planned and all blood was incompatible. Than consulted to Immunology division.

The day seventh, other laboratorium supported revealed low C3 complement (22

g/dL ), positive result for antinuclear antibody (ANA titer >1 : 1000) and Anti-Ds DNA

test (790 IU/mL). Based on SLICC classification criteria, SLE was diagnosed

Patient reffered to pediatric intensive care unit (PICU) and methylprednisolon

pulse intravenous was ruled out at dose 30 mg/kg daily for three day followed by

methylprednisolone intravenous at dose of 2 mg/kg/day. Despite remitting fever

decreased within 48 hours after pulse metylprednisolone, patient condition deteriorated

with respiratory distress 32 times/minutes, tachicadia, oxygen saturation was

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maintenanced by oxygen mask 4 ml/minutes, urine production decreased 0,98 ml/kg/day,

edema anasarka persist, hyponatremia and hypokalemia persist (125 mmol/L and 2,18

mmol/L respectively) . No hypertension revealed. Unfortunatly renal function decreased

abruptly until 49,1 in 3th day treatment (Tabel 2), and haemoglobin level dropping to 4,56

mg/dL. Rapid Progressive Glomerulonephritis (RPGN) diagnosed based on rapid

decrease of GFR start in 8 days hospitalization. Chest X-ray showed cardiomegali and

right pleural efusion. Pericardial effusion and mild tricuspid regurgitation was found on

echocardiography examination (Figure 2) and antifailure therapy needed (furosemid 40

mg intravenous 3 times a day, and spironolactone 25 mg 2 times a day oraly). A life

threatening condition need urgent decision. While guidelines state cyclophosphamide for

lupus nephritis, in our case the patient has severe hemolytic anemia (Hb 3,5 g/dL) hence

choosing cyclophosphamide become a dilemma.

Transfusion was planed to improved haemoglobin level for minimal requirement

cyclophosphamid administration. However patient has positif 4 to donor sera and

autocontrol, prevent the possibility for transfusion. This situation might be explained by

autoimmune hemolytic process which is ussual in SLE patient. However we never found

positif 4 crossmatch in AIHA - SLE related clinical experiences . To make situation

more complex, the local health insurance did not provide support for immunosuppressive

agent for SLE. The risk benefit consideration allowed us to start transfusion with least

positif reaction to donor with diphenhydramine premedication. While waiting the

matched donors, the glomerular filtration rate decreased more (GFR 31,9) as well as

haemoglobin levels (3,5 mg/dL), placing patient in urge for hemodialysis which also did

not possible if anemia was not corrected. This procedure result in successful transfusion

with low reaction and haemoglobin increased to 9,6 g/dL. The other challenging comes

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when we start hidration before cyclophosphamid administration which lead furosemid

administration, which also put patient in worsen preexisting hypocalemia (2,18 mmol/L)

and fluid overload. We decided to give titrated furosemid with closed monitoring.

Cyclophospamide given at low dose 500 mg/bsa/day. Once the cyclophospamide started

monitoring concern to side effect succesfull treatment or disease course was done. We

monitored for patient complaint and vital sign, laboratory for the blood count every 2

weeks, renal function and urine production everyday, electrolyte every 3 days and

SLEDAI score every 3 month..

Table 2. Treatment and renal function test progression

Day of Day Day 7 Day 8 Day 9 Day 10 Day 12 Day 15 Day 18
hospitalization 1 4/7/15 11/7/15
BUN 35 34 50 64 99 95
SC 0,75 0,92 1,98 2,19 2,48 1,45
GFR 103,4 84,3 49,1 35,4 31,3 53,48
Urine Production* 3,9 1,8 1,09 0,79 1,9 2,36
Metylprednosolon 30mg/ 30mg/ 30mg/ 2mg/ 2mg/ 2mg/
intravena kg/day kg/day kg/day kg/day kg/day kg/day
Cyclofosfamid I
(per m2) 500 mg

Day of Day 21 Day 24 Day 25 Day 29 Day 40

hospitalization 21/7/15
BUN 80 65,89 55 38 22
SC 0,91 1 0,72 0,47 0,37
GFR 85,22 77,55 107 165 209
Urine Production* 1,8
Metylprednosolon 2mg 2mg 1mg/ 1mg/ 1mg/
intravena kg/day kg/day kg/day kg/day kg/day
Cyclofosfamid II
(per m2) 500 mg
*ml/kg/day
Six days after first cyclophospamid while metylprednisolone had been 11 days at doses 2

mg/kg/day, blood pressure increased 140/95 mmHg (> P99 + 5 mmHg) accompanied with

halusination, iritable and incoherent. We diagnosed a crisis hipertension. Nifedipine was

taken than maintenanced with amlodipine and furosemide. Altough the blood pressure

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controled, mental status alterd. We consider about neuropsychiatic lupus. He had no

fever, the renal function increased (GFR 85,22), electrolyte showed sodium increased

(133 mmol/L) than potasium at level 2,33 mmol/L. His brain CT – Scan showed normal.

He was treated with haldol 0,5 mg twice a day. Metylprednisolon was tappered over 14

days while he received cyclophosphamid every two weeks. After second

Cyclophospamide RPGN resolved, anemia resolved, serositis resolved, normal liver

fuction test, psychiatric status normal. We did not found cystitis hemoragic nor

neutropenia.

DISCUSSION

SLE is a chronic autoimmune disease that can involve any organ system, and may lead to

significant morbidity and even mortality. It has a wide clinical manifestation variation

and involve any organ. The patients can be ill at presentation and throughout their disease

course. The presentation may mimic many clinical entities and differential diagnosis may

be difficult especially if presentation is atypical. In this case the patient came to

emergency unit with acute generelized edema and dark urine complain. Its seems to be a

nephritic syndrome more over a hypertension grade II and multiple dry impetigo lesion

was found in phisical examination. But this condition did not longer exist. In conjunction

to icterus, disturbance in syntesis, secretion and excretion of liver function, pancytopenia

and imbalace electrolyte displace main foccused to sepsis prosess. But it can’t explained

the followed imunological prosess of anemia and abrupt decreace of renal function

without began haemodinamic failure. Organs affected was unrelated each others. SLE

virtually any organ system, and involvement can be either generalized or isolated.

Constitusional symptoms such as fever, fatique, weight loss are prevalent and common.

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The most common presenting features were mucocutaneus and musculoskeletal

symptoms. In this case we failed to recognized a cronic constitusional symptoms as

lupus features, because these features are not unique to lupus but could be seen in other

infectious, metabolic, malignancy, and other systemic rheumatic diseases. We also failed

to recognize a discoid lesion, mucoulcer and SLE nail discolorisation. Above all, the

patient was male. SLE commonly affected female than male. The sex rasio is 3 : 1 and

increased being 9 : 1 after puberty. About 15-20% of lupus patients, develop their first

symptoms before 18 years of age. In this case the patient was an eleven years old, he was

the first in our department a male with SLE.

The patient was diagnosed with SLE according to SLICC criteria. The presence

of 4 or more of criteria (at least 1 clinical and 1 immunological criteria) or biopsy-proven

lupus nephritis with positive ANA or anti-dsDNA.

Table 3. Systemic Lupus International Collaborating Clinics (SLICC) criteria

CLINICAL CRITERIA
1 Acute Cutaneus Lupus
2 Chronic Cutaneus Lupus
3 Oral Ulcers
4 Non scaring alopesia
5 Synovitis involving ≥ joints
6 Serositis
7 Renal manifestatation
8 Neurological manifestations
9 Hemolytic anemia
10 Leucopenia/Lymphopenia
11 Thrombositopenia
IMMUNOLOGICAL CRITERIA
1 ANA (level above laboratory reference range)
2 Anti-dsDNA
3 Anti-Sm positif
4 Anti Phospolipid Antibody positif
5 Low Complement ( C3, C4, or CH50)
6 Direct Coombs test (in the absence of anemia
haemolytic)

This case was fulfill 9 clinical criteria found discoid rash, oral ulcer, arthritis, serositis,

nephritis, seizure, anemia hemolytic, leucopenia,thrombocytopenia and 2 imunological

criteria ANA and anti-dsDNA positif.

Lupus is thought to result from a combination of hormonal and environmental

factors in a genetically predisposed individual. Ten percent of patients with SLE have a

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first-degree relative who has SLE, and affected patients are more likely to have a family

member who has an autoimmune disease. HLA class II alleles DR2 and DR3 contribute

to disease susceptibility in some patients, as do inherited complement deficiencies, most

commonly homozygous C2 or C4 deficiency. Environmental triggers can be as varied as

infection (parvovirus, Epstein-Barr virus), medication (antihypertensives,

anticonvulsants), hormonal changes (especially sex hormones), and UV light. In this case

there are no family were suffer from SLE.

Children with SLE usually accur with severe form of SLE. According to ACR

guidelines for reveral and management SLE. Patients were subdivided into two groups :

mild SLE and severe SLE.14 Patient with skin, joint, hematologic involvement (apart from

hemolitic and aplastic anemia), serositis were subclassified as having mild SLE. Where

as those with major CNS manifestation, glomerulonephritis, heart and lung parenchymal

manifestation and hemolytic or aplastic anemia were subclassified as having severe SLE.

In this case patient found with RPGN, CNS involvement, anemia aplastic a severe lupus

manifestation.

Children SLE is a more aggressive disease than adult SLE, having a substantially

higher prevalence and severity of nephritis, hematology and CNS disease. The studies

showing that 75-80% of children develop clinically evident nephritis at some point of

their illness. LN is more common in males and non white population. Initial manifestation

of renal disease range from minimal proteinuria, microscopic hematuria to nephritic range

proteinuria, urinary cast, severe hypertension, pheripheral edema, renal insuffisiensy or

acute renal failure. LN is defined as persisten proteinuria 0,5 gram per day or greater than

3+, and/ or cellular cast including red blood cells, granular, tubular or mixed. In

additional, perhaps optimal, criterian is a renal biopsy sample demonstrating immune

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complex mediated glomerulonephris compatible with LN. In this case we found minimal

range proteinuria +1 to +2 with evidence of normal esbach total protein loss (0,48

gram/L/24 hours), besides hematuria (+4 to +5) with granular and amorf sel. This

laboratory founding was not corelated with the patient clinical manifestation with

excessive edema indicates renal biopsy. But this procedure was impossible in our

department. On the day 8 pasient suffered from RPGN the severe form of lupus nephritis.

Rapidly Progressive Glomerulonephritis (RPGN) is a life threatening, severe form of

lupus nefritis. RPGN defined by rapid decrease in the glomerular filtration rate (GFR) of

at least 50% over a short period, from a few days to 3 month, that occurs in 3,6 % in SLE.

In this case the renal function was decreased abruptly in 10 days of hospitalization during

the 3rd methylprednisole pulse dose became 49,1 and fallen until 31,1 at the day 15 (table

2).

Haematological abnormalities are common findings in patients with SLE.

Sometimes, haematological abnormalities can be caused by the pathophysiology of SLE

itself, but at other times they can be found in patients with SLE but not be a manifestation

of SLE. Neither set of criteria, however, specify how leucopenia, lymphopenia and

trombocytophenia in these patients can be differentiated from decreased white cell count

and platelet caused by immunosuppressive therapy or other causes. Thus, it is important

to distinguish haematological abnormalities as either manifestations of SLE, consequence

of SLE treatment or as part of another blood cell dyscrasia. In this case we found both

leucopenia 2,02 x103 K/µL (<4000/ mm3) and lymphopenia 0,36 x103 K/µL (<

1500/mm3) at the first presentation and consisten decreased below the limit criteria more

than 2 occational blood test, and increased after received cyclophospamide. No sepsis

was proven ( the bloodculture revealed no growth). Trombocytophenia found 74 x103

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K/µL (<100.000/mm3) with blood smear shows decreased number of trombocyte and no

clumping, after cyclophospamide trombocyte count revealed normal.

Hemolytic anemia was significanly higher in pediatric than in adult, 14% and 3%

respsctively. The ACR and SLICC criteria recognize AIHA with reticulosytosis as one of

the criteria for classification of SLE, while the SLICC criteria also include a positive

Coomb test as criteria. In this case patient came with anemia normochromic normositer

(Hb 5,4 g/dL; MCV 78 pg; MCH 26,5 pg), reticulocytosis (2,5%), and direct coomb test

positif 4.

Liver involvement is normally not part of the spectrum of SLE, but is seen in up

to 60% of SLE patients. Hepatotoxic drugs, coincident viral hepatitis and non-alcoholic

fatty liver disease (often induced by steroids) are the most commonly described causes of

elevated liver enzymes in SLE. In our case the manifestation of liver was prominant at

the first presentation before treated with steroid. Hepatomegali, icterus, followed by

increased of AST, ALT, Gamma GT level, severe hypoalbumin, and cholestasis with

normal ultrasonography image. This situation also leading us to missdiagnosis, placing

hepatology problem as a prime problem, thought others clinical manifestation was the

followed exertion. As we consult to hepatologic division this process was resume by

autoimune hepatitis after exclusion infection, drug induced, cronic hepatic disease but we

didn’t investigate the IgG total to confirm autoimune hepatitis diagnosed. ANA test will

positif both AIH and SLE. Concurrent AIH as independent disease has not been defined

clearly in patients with SLE. In this case after treated first cyclophospamide the response

was satisfy. Cholestatic resolved, albumin increased, transaminitis resolved.

The current therapeutic strategy for SLE ( severe) nephritis distinguishes two

distinct phases of treatment. The first phase is INDUCTION therapy which aims to

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control disease activity by inducing remission of disease flare (which may be the initial

presentation or represent a new flare). It is at this point that potential organ-threatening

and/or life threatening disease needs to be aggressively treated. The second phase is

MAINTENANCE, where in the target is to avoid relapses and control the disease by

limiting inflammation and damage.

The standard of care has been glucocorticoids, delivered as pulsed therapy and followed

by oral treatment, in combination with cyclophosphamide; however, there remains much

uncertainty about the most efficacious and least toxic steroid doses and how they may be

best used in combination with other newer agents

Cyclophospamid is a representative alkylating agent, induces DNA interstrand

crosslinks, prevents the separation of the strands of the DNA helix, and thus inhibits DNA

replication. Its immunosuppressive effect is thought to be caused mainly by B-cell death.

Reported side effects include digestive symptoms, bone marrow suppression, infection,

hemorrhagic cystitis, gonadal dysfunction, and secondary cancer.

Above all cyclophospamide is importance drug for management of the most severe

aspects of SLE, particulary severe lupus nephritis and CNS disease. Because of its

potential toxicity, however cyclophospamid is not indicated for minor manifestations of

disease and should be used only by experienced clinicians who are familial with the

anticipated benefit and toxicity of this drug. In conjunction with glucocorticoids, its has

been demonstrated to be superior to prednisone alone, especially in severe nephritis. In

this case the patient with severe lupus was treated with metylprednisolone pulse 3 days

and combination with cyclophospamide pulse

Serositis and severe edema was one of the clinical manifestation of our case,

concern of hydration before cyclophospamide hence choice diuretic preparat despite renal

15
function decreased and preexisting hypokalemia while hydration. Diuretic

pharmacokinetic reduce in renal function theoriticaly effect limitation on diuretic

response. There are currently no studies that have directly compared the incidence of

these electrolyte abnormalities between agents, so it is unclear if one agent is most likely

to lead to these disturbances. In this case we use furosemide. Furosemide related adverse

effects can be enhanced in critically ill patients: their labile circulatory system can be

markedly affected by intravascular volume depletion; besides that, electrolyte imbalance

must be avoided. As a matter of fact, First, diuretic pharmacokinetics is in renal,

furosemide administration would uneffective, unusefull to reduce fluid in order reducing

edema anasarka in acute renal failure, hance haemodialysis will become effective choice

in this case but the patient had severe anemia which also hemodialisys didn’t possible if

anemia didn’t corrected. Second, furosemide administration in critically ill patients with

acute renal failure (ARF) has been associated with an increased risk of death and

nonrecovery of renal function. Literature said continuous infusion of furosemide should

have a better safety profile, allowing better hemodynamic stability and less side effects.

We obtained jurnal titled Continous infusion versus bolus injection of furosemide in

critically ill patients. A systemic review and metaanalysis by Zangrilo, et all (2011)

conclude that continous loop diuretic initial by loading dose were more increased diuresis

volume achivement in adult with overload than intermitten boluses. But in 3 children

studies were showed no increased diuresis volume.

In our case patient was threated with continous furosemid with doses 1 mg/kg/day while

hydration, diuresis volume achivement is 0,78 – 1,7 ml/kg/day, no haemodinamic

disturbance and no electrolyte changes before and after treatment.

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 Monitoring of complete blood counts is essential during cyclophosphamide

treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be

administered to patients with neutrophils ≤1,500/mm3 and platelets < 50,000/mm3.

Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose

reduced, in patients who have or who develop a serious infection. G-CSF may be

administered to reduce the risks of neutropenia complications associated with

cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be

considered in all patients considered to be at increased risk for neutropenia complications.

The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached

in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after

approximately 20 days. Bone marrow failure has been reported. Severe

myelosuppression may be expected particularly in patients pretreated with and/or

receiving concomitant chemotherapy and/or radiation therapy. In this case the neutrophil

count was 1,4 x 103 K/µL and the thrombocyte is 74 x 103 K/µL. Nine days after first

cyclophosphamide neutrophil was 7,01 x 103 K/µL and thrombocyte was 92 x 103 K/µL,

both increased when discharge.

The new challenge came after 1st cyclophospamide conducted while patient also

on steroid high doses, patient complaint of neuropsyciatric symptoms headache,

halusination, and agitation. We consider if those condition was related to SLE or the

excessive effect of steroid. A brain CT-Scan was done and showed normal. Literature

said that neuropsyciatric simptom are common in SLE, 65% of patients developed a

neuropsychiatric lupus at the course of disease and 85% in within 2 years from diagnosis.

Common symptoms are headache, depressive affect, impairment of cognition, psychosis,

confusion, seizure, and stroke, and peripheral nervous system involvement is less

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frequent. Older journal said that most of neuropsyciatric simptom in SLE, 60% is related

to metylprednisolone treatment. We didn’t found journal described the risk of

neuropsyciatric simptom in SLE pediatric with and without metylprednisolon treatment.

The newest otherwise. A retrospective observational study of adult SLE threated with

combination cyclophospamide in and glucocorticoids for severe neuropsychiatric

systemic lupus erithematosus showed that 46% pasien were positive for antiphospolipid

antibodies (aPL). Is aPL associated with NPSLE ? we found journal title Neuropsikiatric

manifestations in systemic lupus erythematosus: prevalence and association with

antiphospolipid antibody. This study described that antiphospolipid antibody were

independently associated with cerebrovaskular disease (OR 6,17, 95% CI 2,94 – 12,9,p

= 0,001) headache (OR 2,89, 95% CI 1,17 – 3,55,p = 0,01), and seizure (OR 2,98 95%

CI 1,18 – 1,10 p = 0,02) The new criteria for NPSLE are useful to define NP manifestation

accuracy. NP manifestation are significanly association with aPL. In our case it is we

did not run this aPL axamination because because test had not been available in Indonesia.

SUMMARY

An 11 years old male diagnose with SLE after 7 days hospitalization for unexplained

condition of prolonged febris, pansitopenia, edema anasarca, serositis, acute liver injury,

AKI failure, hypertension grade II, imbalance electrolyte, seizures. Metylprednisolone

pulse dose was conducted for 3 days followed by doses 2 mg/kg/day. But the disease

course was uncontrolled lead worsening multiorgan disfunction during the treatment.

RPGN raised just in 8 days of hospitalization accompanied by severe anemia hemolytic,

serositis and severe edema, placing a life threatening condition. Cyclophospamide must

ruled out. Consideration its strong immunosupresif effect but high cell toxicity, life saving

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 had to be most reason. Taking risk in giving transfusion to reached minimal requirement

haemoglobin level cyclophopamide administration. Taking risk hidration on overload

condition and renal failure before cyclophospamide. Challege in identifiying new CNS

simptom as a part of lupus disease versus side effect while patient on steroid.

After second CYD admiistration, multiorgan disfunction was resolved.

REFERENCES

1. Weiss JE. Pediatric systemic lupus erythematosus: more than a positive antinuclear

antibody. Pediatric in review. Colagen vascular. 2012;33:61-73.

2. Minaa R, Brunner H. Pediatric lupus-are there differences in presentation, genetic,

response to therapy, damage accrual compared to adult lupus? Rheum Dis Clin North

Am. 2010; 36(1):53-80

3. Hersh AO, Trupin L, Yazdany J, et al. Childhood-onset disease predicts mortality in an

adult cohort of patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken).

2010;62(8):1154-9.

4. Thakral A, Klein-Gitelman MS. An update on treatment and management of pediatric

systemic lupus erythematosus. Rheumatol Ther. 2016;3:209-19

5. Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents.

Pediatr Clin North Am. 2012;59(2):345-64.

6. Tucker LB. Making diagnosis of systemic lupus erythematosus in children and

adolescents. Lupus. 2007;16: 546-9.

19
7. Balacandran A, Mathew AJ. SLICC classification criteria for SLE. Evidence based

medicine. 2015.

8. Bertsias G, Cervera R, Boumpas DT. Systemic Lupus Erythematosus: Pathogenesis and

clinical features. EULAR Textbook on Rheumatic Disease. 2012;20:476-505.

9. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of

systemic lupus erytematosus. Arthritis Rheum. 1982; 25:1271-7.

10. Gladman DD, Urowitz MB. In: Wallace DJ, Hahn BH, Dubois , editors. Prognosis,

mortality and morbidity in systemic lupus erythematosus. Lupus Erythematosus. 6th

edition. Philadelphia: Lippicott Williams and Wilkins; 2002. p. 1255-73.

11. Sumethkul V, Chalersanyakorn P, Changsirikulchai S, Radinahamed P. Lupus nephritis:

a challenging cause of rapidly progressive crescentic glomerulonephritis. Lupus

2000;9(6):424-8.

12. Greenhall GHB, Salama AD. What is new in the management of rapidly progressive

glomerulonephritis? Clin Kidney J. 2015;10:1-8.

13. Fayyaz A, Igoe A, Kurien BT, et al. Hematological manifestation of lupus. Lupus Science

and medicine. 2015.

14. Vachvanichsanong P, Dissaneewate EM. Intravenous cyclophospamide combined with

steroids in pediatric onset severe lupus nephritis. Nephrology. 2013.

15. Granado RC-D, Mehta R. Fluid overload in ICU: evaluation and management. BioMed

Central.2016

16. Zangrilo et al. Continous infusion versus bolus injection of furosemide in critically ill

patients. A systemic review and metaanalysis.

17. Fanouriakis A, Pamfil C, Sidiropoulos P. Cyclophospamide in combination with

glucocorticoids for severe neurophychiatric systemic lupus erythematosus. Lupus. 2015

20
18. Harel L, Sandborg C, Tzielan L, et al. Neuropsikiatric manifestations in systemic lupus

erythematosus: prevalence and association with antiphospolipid antibody. The Journal

of Rheumatology. 2006;33:1873-7

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