Corticosteroid Pulse Therapy for the Treatment of Bullous Systemic

Lupus Erythematosus with Lupus Nephritis

Hayra Diah Avianggi

, Intan Nurmawati

, Radityastuti

, Widyawati

, Meira Dewi Kusuma

Departmentof Dermatovenereology, Faculty of Medicine, Diponegoro University /

dr. Kariadi General Hospital, Semarang

Department of Pathology Anatomical, Faculty of Medicine, Diponegoro University /

dr. Kariadi General Hospital, Semarang

*Corresponding author

Keywords: Bullous systemic lupus erythematosus, SLICC criteria, corticosteroid pulse therapy, lupus nephritis

Abstract: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Skin involvement occurs in

nearly 76 % of all lupus patients. The Bullous Systemic Lupus Erythematosus (BSLE) is a rare cutaneous

variant of SLE, affecting in less than 1%. A26-year-old female with a history of a vesiculobullous eruption

on face, neck, trunks, andarms, along with oral mucosa ulcers.She hadphotosensitivity, a non-scarring

alopecia, hemolytic anemia, serositis, arthralgia, renal impairment, and high antibody titers confirmingSLE.

Histopathologicalexamination showed features in accordance with SLE, tends to beBSLE. The renal biopsy

confirmed the features of lupus nephritis. The patient was diagnosed as BSLE based on the Systemic Lupus

International Collaborating Clinics (SLICC) criteria, location of a blister, and histopathologicfinding. She

responded well to systemic corticosteroid pulse therapy. BSLE should be considered as a differential

diagnosis among patients with bullous lesions.It is vital to prevent the complication of SLE, that is lupus

nephritis because it relates to a worse prognosis. We choose corticosteroid given as pulsed therapy to

enhance the therapeutic effect and reduce the side effects, followed by azathioprine as sparing agent.

Systemic corticosteroid pulse therapy is considered as first-line therapy, with azathioprine which has been

proved to be effective in maintaining disease remission. The objectiveof BSLE therapy is to prevent new

blisters, promote healing, and prevent scarring.Prognosis ad vitamdubiaadbonam, ad sanamdubiaadmalam,

ad cosmetic dubiaadbonam.

1 INTRODUCTION

The systemic lupus erythematosus (SLE) is a

multisystem autoimmune disease. The bullous

systemic lupus erythematosus (BSLE) is a rare

cutaneous variant of SLE, accounts less than 1%.

BSLE is an autoantibody-mediated vesiculobullous

disease in patients with SLE (Chen et al, 2015). The

etiology of BSLE is unclear (Contestable et al,

2014). In the USA there is an association between

SLE with HLA-DR2 (Wojnarowska et al, 2010;

James et al, 2016). BSLE usually manifests in the

second and third decades of life, most frequently in

black women (Momen et al, 2016). If there is a

bullous eruption, we have to consider BSLE as a

differential diagnosis. Multiple case reports show

that BSLE can be the initial presentation of SLE

(Contestable et al, 2014; Momen et al, 2016). Here

in we report a case of BSLE treated with

corticosteroid pulse therapyas an alternative therapy

to Dapsone.

2 CASE

A 26-year-old female was admitted to emergency

department Dr. Kariadi General Hospital with a 1-

week history of a progressive non-itching blistering

eruption, erosion and crust around the face, neck,

trunks, and arms. She also complained of diffuse

hair loss, moderate fever, and arthralgias for the last

three months. Bullae have appeared on the sun-

exposed areas with the erythematous base while

those on the arms had a clear base. There were

histories of malar rash after sun exposure and

conjunctivitis on the right eye. She has never had

Avianggi, H., Nurmawati, I., Radityastuti, ., Widyawati, . and Kusuma, M.

Corticosteroid Pulse Therapy for the Treatment of Bullous Systemic Lupus Erythematosus with Lupus Nephritis.

DOI: 10.5220/0009988803570361

In Proceedings of the 2nd International Conference on Tropical Medicine and Infectious Disease (ICTROMI 2019), pages 357-361

ISBN: 978-989-758-469-5

357

any seizure, psychosis, and history of blistering

lesions before. She was not taking any drugs and

never had a drug allergy. There is no family member

with the same complaint. She weighed 42 kg with a

height of 150 cm. Clinical examination revealed

poor nutritional status with moderate pallor, bilateral

pitting pedal edema with facial puffiness, and

temperature (37.8°C). Her pulse rate was 92/min,

Blood pressure was 110/70 mmHg, and respiration

rate was 20/min. There was no enlargementon liver,

spleen, and lymph node. The anogenital regions

were spared. The dermatologicexamination

demonstrated erosion and crusts on face, neck,

trunks, and arms (Figure.1 A, B, C, D).Diffuse hair

loss (Figure.1 E). Curdy white discharge was seen

over the oral ulcers (Figure.1 F).

Figure 1. A. Erosion and crusts on the face, conjunctivitis on right eye (B, C, D) Erosion and crusts on the neck, trunks, and

arms,E. Diffuse hair loss,F. Oral ulcers, and crust.

Based on the anamnesis and physical

examination, there were several differential

diagnoses: bullous systemic lupus erythematosus

(BSLE) andpemphigus erythematosus with SLE

(Senear-Usher syndrome). She was referred to the

Department of Nephrology for kidney

biopsy.Laboratory examination shows (Table.1).

Table.1. Laboratory examination

EXAMINATION RESULT

Hematology

- Haemoglobin 8,5 g/dL, increase RDW 16,4%

- Leukopenia 3,7x10

/UL, lymphopenia 3%

Blood

Biochemistry

- Increased serum creatinine 2,08 mg/dl and (Duplo test)

- Increased serum ureum 188 mg/dl (Duplo test).

- Creatinine clearance 30ml/min. Hypoalbuminemia (2,4 g/dl)

- Random Glucose Test (GDS), SGOT and SGPT within normal limits

Peripheral blood

smear

- Anisocytosis, poikilocytosis (ovalosit, pearshape, teardrop, burr cell).

Chest X-RAY

- Cardiomegaly (LV, LA)

ECG

- Pericardial effusion with LvH concentric, no features of Myocarditis

USG

- Pleura effusion sinistra

- Bilateral cortical echogenicity increased, suggestive of renal parenchymal disease

(Brenbridge 1).

Urine Routine

- Proteinuria 15mg/dl, Reduction 500mg/dl

- Leukocyte sediment 232,1/ul, leukocyte 25-30 LPB, glitter cell (+), cylinder

3,22/ul, hyaline cylinder 3,5 /ul

- Yeast cell 82,3/ul.Bacteria 7177,6/ul (++).

- Urinesbach 0 g/L volume 350 cc in 24 hour

Immunology test

- Serum anti-nuclear antibodies (ANA) 268,7 unit (> 60 positive)

- Anti double-stranded DNA (Anti dsDNA) 1098 IU/ml (> 300 Positive)

Serologic test

- Venereal Disease Research Laboratory (VDRL), HBsAg, and Human

immunodeficiency virus (HIV) were negative. CD4: 137.

Histopathology

examination

- Granulosis, spongiosis, and degeneration vacuolar(Figure 2A).

- Fibrous stromascattered with lymphocytes, histiocytes, perivascular in the

papillary dermis(Figure 2B).

Kidney biopsy

- Diffuse Lupus Nephritis Class IV of ISN/RPS 2004 classification with an active

lesion (Figure 2C).

ICTROMI 2019 - The 2nd International Conference on Tropical Medicine and Infectious Disease

358

Based on anamnesis, physical examination, and

laboratory examination, the patient was diagnosed as

Bullous systemic lupus erythematosuswith lupus

nephritis and oral thrush. The patient was managed

with methylprednisolonepulse therapy 500mg/day

(equivalent to prednisone 15 mg/kg/day) IV for three

consecutive days, followed by half adjusting dose

every three days until 32 mg/day orally (equivalent

to prednisone 1 mg/kg/day) for one week.

Azathioprine was started with 50 mg once daily

peroral, ranitidine 150 mg twice a day IV, and

systemic broad-spectrum antibiotics (ciprofloxacin)

500 mg twice a day, folic acid 1 mg once daily. The

lesion was soaked with 0.9% NaCl for ± 15 minutes

before the use of fusidic acid cream and silver

sulfadiazine cream twice a day to erosions and

crusts, nystatin drop 100,000 UI, 1cc / 8 hours for

lesions in the oral cavity and triamcinolone

acetonide in orabase. The results of the therapy are

quite satisfactory. The patient is also given a whole

blood transfusion to treat anemia. The patient was

referred to Department of Nephrology for the

treatment of lupus nephritis, and she was put on

cyclophosphamide and lisinopril. She was

discharged with no new skin lesions after 20

days.(Figure 2 D,E,F,G, H).

Figure 2. A.The epidermis, granulosis, spongiosis and degeneration vacuolarB. Dermis; subepidermalvesiculation, fibrous

stromascattered with lymphocytes, histiocytes and perivascular inpapillary dermisC. Diffuse Lupus Nephritis Class IVD, E,

F, G. Hyperpigmentedmacula on the face, neck, trunks, and arms H. No sign of oral ulcers

The patient was advised to visit a dermato-

venereology clinic every two weeks to monitor side

effects due to the long-term of topical and systemic

corticosteroids, to do periodic blood, urine and

serology tests, and to always use a sunscreen with

SPF ≥30, 20 minutes before sun exposure.

3 DISCUSSION

The bullous systemic lupus erythematosus (BSLE) is

a rare autoimmune blistering disorder that typically

manifests as a vesiculobullous eruption in a patient

with SLE.(Contestable et al, 2014) Clinically, BSLE

is characterized by rapid onset of widespread, tense,

clear or hemorrhagic fluid containing vesicles to

bullae which rupture spontaneously resulting in

erosions and crusts. These blisters are distributed

over the neck, face, trunks, and extremities.The

occurrence of blisters on the healthy skin should

always arouse suspicion of BSLE. (Chen et al, 2015)

The diagnostic criteria of BSLE were ﬁrst

described by Camisa and Sharma in 1983 and were

revised in 1988. These criteria were (1) diagnosis of

SLE based on ACR criteria; (2) vesicles and/or

bullae; (3) The histopathology is characterized by

subepidermal bullae with microabscesses of

neutrophils in the dermal papillae; (4) DIF with IgG

and/or IgM and often IgA at the BMZ; and (5) IIF

testing that can be negative or positive for

circulating autoantibodies against the BMZ via the

salt-split skin technique. (Contestable et al, 2014)

The American College of Rheumatology

(ACR) revised criteria for SLE in 1997, which were

recently validated by the Systemic Lupus

International Collaborating Clinic (SLICC) group in

2012 that results in higher sensitivity with equal

specificity (Table 2).(Kuhn et al, 2015)

Corticosteroid Pulse Therapy for the Treatment of Bullous Systemic Lupus Erythematosus with Lupus Nephritis

359

Table 2. Classification of SLE based on the Systemic Lupus International Collaborating Clinic (SLICC) Criteria,

and case

Classification of SLE: The Systemic Lupus International

Collaborating Clinic (SLICC) Criteria

Case

Clinical criteria

- The acute cutaneous lupus erythematosus (butterfly rash)

- The chronic cutaneous lupus erythematosus (discoid LE)

- Oral ulcers

- Non-scarring alope

cia

- Synovitis (≥ 2 joints) or tenderness on palpation (≥ 2 joints)

and morning stiffness (≥ 30 minutes)

- Serositis (pleurisy / pericardial pain for > 1 day)

- Renal involvement (single urine: protein/ creatinine ratio/24-

hour urine protein >0,5g)

- Neurological involvement (seizures, psychosis)

- Hemolytic anemia

- Leukopenia (<4000/µL) or lymphopenia (<1000/µL)

- Thrombocytopenia (<100.000/µL)

Clinical criteria

- Butterfly rash positive

- Negative

- Oral ulcers positive

- Positive, 3 months ago

- Arthralgia (ankle, interdigital)

- Pericardial and pleural effusion

- Proteinuria 15 mg/dl and Creatinine

clearance 30 ml/min.

- Negative

- Anemia normositiknormokrom

- Leukopenia 3,7x10

/UL

- Within normal limits

Immunological criteria

- ANA level; above laboratory reference range

- Anti-dsDNA antibodies

- Anti-sm antibodies

- Antiphopolipid antibodies (anticardiolipin and anti-β2-

glycoprotein I antibodies, false-positive VDRL test

- Low complement (C3, C4, or CH50)

- Direct coombs (in the absence of hemolytic anemia)

Immunological criteria

- ANA 268,7 unit (Positive > 60)

- Anti dsDNA 1098 IU/ml (Positive >

300)

- No examination

- VDRL negative

- No examination

(References: The Diagnosis and Treatment of Systemic Lupus Erythematosus)

According to the SLICC rule, the patient must

manifest at least four criteria (including at least one

clinical criterion and one immunologic criterion) or

must have biopsy-proven lupus nephritis in the

presence of either ANAs or anti-dsDNA antibodies

(Contestable et al, 2014; Kuhn et al, 2015)

Thehistopathological section in trunks erosion

showed old lesion, and the feature view shows a

central focus of degeneration vacuolar,

subepidermalvesiculation, striking inflammatory

changes outline the dermal vasculature. This is in

accordance with the other features of BSLE(Calonje

et al, 2012). Skin biopsy report only to corroborate

our clinical impression and to form our final

diagnosis. (Momen et al,2016)

Differential diagnosis of BSLE is pemphigus

erythematosus with SLE (Senear-Usher syndrome).

Senear-Usher syndrome can be ruled out because it

is an autoimmune condition where there is overlap

between the clinical and immunological features of

pemphigus erythematosus and lupus erythematosus,

include like scattered scaly flaccid blisters with

erosions and crusts on ‘seborrhoeic’ areas along with

malar rash, absence of mucous membrane

involvement. ANA test is negative or weakly

positive. Histopathological showedacanthotic

epidermis with large subcorneal blisters.(Amatya et

al,2017)

Dapsone is the initial treatment of choice for

BSLE. (Contestable et al, 2014) The mechanism of

actionmainly relies upon its inhibition of the

functions of PMN leukocytes and of complement

activation via the alternative pathway that has been

postulated. (Chen et al, 2015) We didn't choose

dapsone due to patient‘s hemolytic anemia and its

unavailability in our facility. A corticosteroid may

be active in patients who cannot tolerate dapsone,

have an inadequate response to dapsone, or require

treatment of concurrent systemic manifestations of

systemic lupus erythematosus. (Visser et al, 2017)

Based on recommendations of GRh (German

Society of Rheumatology) where corticosteroids as

first-line therapy, begin with methylprednisolone

500–750 mg iv on three consecutive days (level of

evidence 3, the strength of statement C); then per os

0.5 mg/kg body weight/day for four weeks with

subsequent tapering.

Corticosteroid pulse therapy

means it refers to treatment with more than 250 mg

prednisone or its equivalent per day, for one or more

days.The effects of corticosteroid pulse therapy

appear to include downregulation of activation of

immune cells and proinflammatory cytokine

production, leading to reduced expression of

ICTROMI 2019 - The 2nd International Conference on Tropical Medicine and Infectious Disease

360

adhesion molecules and reduced movement of

neutrophils into sites of inflammation. (Visser et al,

2017;Panat,2012) On this patient, we used

methylprednisolone intermediate-acting with a low

tendency to induce sodium and water retention.

When decreasing corticosteroid doses, treatment

with a sparing agent (azathioprine) regimen

begins..(Visser et al, 2017) The aim of corticosteroid

pulse therapy is getting quicker and stronger efficacy

and decreasing the need for long-term use of

steroids. (Panat,2012)

Azathioprinehas proved to be effective in

maintaining disease remission. (Chen et al, 2015) It

is a purine analog that inhibits the nucleic acid

synthesis and affects both cellular and humoral

immune functions. The drug is transformed to 6-

mercaptopurine (6-MP) and then to its active

metabolites, thiocyanic and thioguanine acid (6

TGN), which incorporate into DNA, thereby causing

DNA/protein crosslinks and interfering with nucleic

acid structure. The daily dose is 1 - 2.5 mg/kg.

Regular monitoring of complete blood counts and

liver function tests is required during therapy.(Visser

et al, 2017)

Prognosis of this patient was ad

vitamdubiaadbonam, ad sanamdubiaadmalam, ad

cosmetic dubiaadbonam. The course of BSLE is

often remitting. The disorder frequently resolves

spontaneously in less than one year. BSLE is an

autoimmune disease that tends to relapse. In some

cases, post-inflammatory hypopigmentation may

remain. The development of BSLE in patients with

SLE does not typically lead to increased mortality.

Morbidity depends on the extent of the eruption and

the response to therapy.(Chen et al,

2015;Contestable et al, 2014; Kuhn et al, 2015).

4 CONCLUSION

BSLE should be considered as a differential

diagnosis of patients with bullous lesions.

Differentiation between BSLE and other blister

disease is vital to prevent further complications of

SLE that may coexist. Corticosteroid pulse therapy

proved can be given as an alternative to Dapsone in

BSLE with nephritis lupus.

REFERENCES

Amatya B, Mm AS, Maharjan L. 2017. Dermatology Case

Reports Pemphigus Erythematosus in a Middle Aged

Nepali Male : Case Report and Literature Review.

2(1):2–4.

Calonje Eduardo; Brenn Thomas; Lazar Alexander;

McKee Phillip, editor. 2012. Of the Skin. In: McKEE’s

Pathology Of The Skin With Clinical Correlations.

Fourth. British: Elsevier Saunders. p. 99–150.

Chen J, Zhong S, He Y, Wang Y, Shi G, Duan L, et

al. 2015. Treatment of Bullous Systemic Lupus

Erythematosus. J Immunol Res.m. 2015:1–6.

Contestable JJ, Edhegard KD, Meyerle JH. 2014.

Bullous Systemic Lupus Erythematosus: A

Review and Update to Diagnosis and Treatment.

Am J Clin Dermatol. 15(6):517–24.

James W, Berger T, Elston D NI. 2016. Connective

Tissue Disease. In: Andrews’ Diseases of The

Skin Clinical Dermatology. Twelfth. USA. p.

153–64.

Kuhn A, Bonsmann G, Anders HJ, Herzer P,

Tenbrock K, Schneider M. 2015. The Diagnosis

and Treatment of Systemic Lupus Erythematosus.

Dtsch Arztebl Int. 112(25):423–32.

Momen T, Madihi Y. 2016. Bullous systemic lupus

erythematosus and lupus nephritis in a young

girl. Oman Med J. 31(6):453–5.

Panat SR, Aggarwal A, Joshi A. 2012. Pulse

Therapy : A Boon or Bane. (May):3–5.

Visser K, Houssiau FA, Antonio J, Silva P. 2017.

Systemic lupus erythematosus : treatment.

Module 18. EULAR.

Wojnarowska, F. Venning V. 2010. Immunobullous

Diseases. In: Tony Burns, Stephen Breathnach

CG ths and NC, editor. Rooks Textbook of

Dermatology Dermatology. eight edit. USA. p.

1895–957.

Corticosteroid Pulse Therapy for the Treatment of Bullous Systemic Lupus Erythematosus with Lupus Nephritis

361