A case of bullous systemic lupus erythematosus: Diagnostic challenges and clinical implications

Key Clinical Message

Skin involvement in systemic lupus erythematosus (SLE) is common. Bullous lesions in SLE patients are usually due to other autoimmune conditions or rarely, due to lupus itself. Bullous SLE is rare blistering disorder characterized by subepidermal blisters. We, hereby, present a case of bullous SLE in a 24‐year‐old female who responded well to systemic glucocorticoids, mycophenolate mofetil, and dapsone.

Bullous systemic lupus erythematosus (SLE) is a rare blistering disorder associated with SLE, and clinicians should consider it in the differential diagnosis of bullous skin lesions in patients with established or suspected SLE.

1. INTRODUCTION

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple systems in the body. The disease is characterized by a wide range of cutaneous manifestations. ¹ The prevalence of skin involvement in SLE is reported to be approximately 76% during the course of the disease. ² One of the less frequently observed cutaneous manifestations of SLE is bullous skin lesions, which occur in less than 1% of patients with SLE. ³

Bullous systemic lupus erythematosus (BSLE) is a blistering disease characterized by tense subepidermal fluid‐filled vesicles and bullae. The common sites of involvement include the face, trunk, neck, extensor surfaces of upper limbs, and oral mucosa. ⁴ It may present in a spectrum as a small group of vesicles to large tense blisters. ⁵

Pedro and Dahl described the first case of BSLE. ⁵ Bullous lesions observed in SLE patients may not necessarily be indicative of bullous systemic lupus erythematosus (BSLE). In order to differentiate BSLE from other forms of bullous lesions, a diagnostic criterion was initially proposed by Camisa and Sharma, ⁶ followed by the classification of BSLE into two subtypes by Gammon and Briggaman based on the presence of antibodies in circulation. ⁷ The diagnostic criteria for BSLE consist of five key elements. The diagnostic criteria for Type I BSLE necessitates the presence of all five of the criteria. ⁷ Bullous SLE has also been rarely associated with erosions in esophagus. ⁸ In this report, we present a case study of a 24‐year‐old Southeast Asian female with Type I BSLE.

2. CASE PRESENTATION

A 24‐year‐old female patient presented to the emergency department with pruritic blisters and bullae on both hands, which had been present for 2 months. The lesions initially appeared as pruritic plaque and eventually involved the entire face and trunk. The patient also reported weight loss, myalgia, fatigue, intermittent fever, self‐limiting epistaxis, and hair loss. She denied experiencing exertional dyspnea, hematuria, decreased urine output, proximal muscle weakness, joint pain, or recent drug intake.

On examination, the patient's vital signs were within normal limits with a respiratory rate of 22 breaths per minute, a pulse rate of 112 beats per minute, and a blood pressure of 80/60 mmHg. Her oxygen saturation level was 96% on room air. Physical exam showed non‐cicatricial hair loss (Figure 1), pallor, a malar rash with nasolabial sparing, and a discoid rash in bilateral ears. The patient exhibited numerous tense clear vesicles and bullae with an erythematous base on her face, nape of the neck, trunk (Figure 2), and bilateral hands. Additionally, superficial erosions and a few superficial scars were observed, along with positive Bulla spread sign and Nikolsky sign. Multiple superficial erosions were also present in the buccal mucosa, hard palate, and lips. Remaining physical examination was normal.

FIGURE 1.

Non‐cicatricial hair loss.

FIGURE 2.

Multiple bullous lesions in the back with erosions.

The differential diagnosis include bullous pemphigoid (BP), BSLE, epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH). The significant laboratory findings are enlisted in Table 1.

TABLE 1.

Notable investigations profile of patient.

Test/investigation	Results
Leucopenia	2600/mm3
Anemia	Hemoglobin level: 8.1 gm/dL
Transaminitis	SGOT: 194 U/L, SGPT: 53 U/L
Hypoalbuminemia	2.9 gm/L
Urine routine examination	Active sediments, white blood cells, albumin
24‐h urine protein examination	Proteinuria: 0.42 gm/24 h
Peripheral blood smear	Microcytic hypochromic anemia, pencil, and teardrop cells
Antinuclear antibody (ANA)	Significantly positive, titer unspecified
Erythrocyte sedimentation rate (ESR)	18 mm/h
C‐reactive protein (CRP)	1.8 mg/L (normal range: 0–4.8 mg/L)
Complement levels	Slightly decreased
Direct immunofluorescence	Strong C1q positivity, IgG, and IgA positivity
Anti‐RNP antibody	Strong positive
Anti‐Smith antibody	Strong positive
Ribosomal protein	Strong positive
Anti‐centromere antibody	Negative
Anti‐topoisomerase‐1 (anti‐SCL‐70) Antibody	Negative
Anti‐Jo‐1 antibody	Negative
Anti‐SSA antibody	Negative
Anti‐SSB antibody	Negative
ANCA panel	Negative

Initial investigations revealed leucopenia (2600/mm³), anemia with a hemoglobin level of 8.1 g/dL, transaminitis (SGOT‐194 U/L and SGPT‐53 U/L), and hypoalbuminemia (2.9 gm/L). The urine examination indicated active sediments with an abundance of white blood cells and albumin. The 24‐h urine protein examination demonstrated proteinuria (0.42 gm/24 h). Furthermore, the peripheral blood smear exhibited microcytic hypochromic anemia with pencil and teardrop cells.

The patient's autoimmune workup demonstrated a significantly positive antinuclear antibody (ANA) result. Additionally, her erythrocyte sedimentation rate (ESR) was 18 mm/h, and her C‐reactive protein (CRP) was 1.8 mg/L (with a normal range of 0–4.8 mg/L). Complement levels were slightly decreased. The histopathological examination of skin showed subepidermal blistering accompanied by a dense neutrophilic infiltration (Figure 3).

FIGURE 3.

Histopathology showing subepidermal blistering with neutrophilic infiltration in upper dermis.

Direct immunofluorescence (DIF) conducted on a skin biopsy revealed strong C1q positivity, along with IgG and IgA positivity, which supports the diagnosis of lupus (Figure 4).

FIGURE 4.

Immunofluorescence demonstrated linear pattern along basement membrane zone with strong C1q positivity, IgG, and IgA positivity.

Further tests for anti‐RNP antibody, anti‐Smith antibody, and ribosomal protein demonstrated strong positive results. However, anti‐centromere antibody, anti‐Jo‐1 antibody, anti‐topoisomerase‐1 (anti‐SCL‐70), anti‐SSA antibody, and anti‐SSB antibody were negative. The antineutrophil cytoplasmic antibody (ANCA) panel was also negative.

The patient was administered glucocorticoids at a dose of 1 mg/kg/d, in addition to hydroxychloroquine at 200 mg/d, dapsone, and mycophenolate mofetil. Following 1 week of treatment, there was a notable improvement in the patient's skin lesions and other symptoms. The patient did not experience any relapse during their hospitalization or at the 3‐month follow‐up.

3. DISCUSSION

BSLE is a relatively infrequent manifestation of SLE, and it predominantly affects women in the age range of their second to fourth decade ⁸ , ⁹ , ¹⁰ , ¹¹ as was the case with our patient.

Its pathophysiology involves the development of autoantibodies against Type VII collagen, specifically the non‐collagenous domain Type 1 and 2 (NC1 and NC2) of Type VII collagen ¹¹ present in the basement membrane zone (BMZ) that plays a crucial role in anchoring fibril attachment between the epidermis and dermis. The subsequent weakened adhesion of the basement membrane to the dermis results in subepidermal blistering. Additionally, autoantibodies against other proteins such as BPAg1, laminin 5, laminin 6, and BPAg2 have also been identified. ¹¹

BSLE patients typically present with tense blisters in the facial, cervical, and upper limb regions, as well as in the oral mucosa, particularly on the hard palate and vermilion border. These blisters may appear in both sun‐exposed and nonexposed areas. Notably, these blisters do not leave scars upon healing. ¹² , ¹³ Our patient exhibited similar clinical features.

The histopathological examination of BSLE typically shows subepidermal blistering accompanied by a dense neutrophilic infiltration, often accompanied by micro‐abscesses in the dermal papillae, ¹⁰ which is consistent with the observations made in our case.

Immunopathological studies have revealed DIF to show linear IgG deposits at the BMZ in BSLE, with occasional granular IgA, IgM, and C3 deposits. ¹⁴ , ¹⁵ Salt‐split skin indirect immunofluorescence (IIF) has also been used to demonstrate IgG deposition at the dermal side of cleavage. In addition, the presence of autoantibodies against Type VII collagen can also be detected in patients with this condition. ¹⁶

The BSLE diagnostic criteria, delineated by Camisa and Sharma, and refined by Gammon and Briggaman, ⁷ comprise a comprehensive set of guidelines. The diagnostic criteria for BSLE consist of five key elements. ⁵ , ⁷

1. Patients must fulfill the criteria for SLE established by the American College of Rheumatology.

2. A crucial characteristic of BSLE is the presence of an acquired vesiculobullous eruption, which serves as a prominent clinical marker.

3. Histologic examination is vital, with skin biopsies revealing evidence of a subepidermal blister and a predominant neutrophilic dermal infiltrate, confirming the disease pathology.

4. Immunological assessments play a significant role; DIF microscopy should demonstrate deposits of immunoglobulin (Ig) G at the BMZ, potentially accompanied by IgA and IgM.

5. The presence of antibodies targeting Type VII collagen must be confirmed through various methods, including DIF or IIF on salt‐split skin, immunoblotting, immunoprecipitation, enzyme‐linked immunosorbent assay (ELISA), or immunoelectron microscopy, solidifying the autoimmune response against collagen Type VII.

Our patient met the fundamental criteria for SLE as established by the American College of Rheumatology. In addition to this, our patient presented with a distinct vesiculobullous skin eruption, marked by clear vesicles and bullae with an erythematous base on her face, neck, trunk, and hands. A thorough histological analysis and DIF microscopy on a skin biopsy solidified the diagnosis of BSLE. Although specific testing for antibodies to Type VII collagen was not conducted, the patient's clinical presentation, histopathological features, and immunofluorescence findings provided substantial support for the BSLE diagnosis.

Therefore, our patient's case satisfies each of the criteria for a BSLE diagnosis. These compelling correlations between the patient's clinical manifestations and the established diagnostic criteria form a robust foundation for our diagnosis and underscore the uniqueness of this case within the spectrum of autoimmune blistering disorders.

In this case, the differential diagnosis encompassed several blistering conditions, such as DH, EBA, BP, and linear IgA bullous dermatosis. While certain distinguishing features may not be universal among the diagnoses, they can aid in the thorough exclusion of other blistering diseases, as outlined in Table 2.

TABLE 2.

Differential diagnoses of BSLE along with their immunofluorescence and histopathological features.

Diagnosis	Clinical features	Immunofluorescence	Histopathology
Bullous lupus erythematosus	Presence of SLE (ACR or SLICC criteria); predilection to sun‐exposed and unexposed skin and mucosa	Strong C1q positivity, along with granular IgG and IgA deposits in the dermo‐epidermal junction	Diffuse neutrophilic infiltration in papillary dermis
Dermatitis herpetiformis	Predilection to extensor surfaces, elbows, knees, and buttocks; intensely pruritic	Granular deposition of IgA	Accumulation of neutrophils in papillary dermis
Epidermolysis bullosa acquisita	Absence of SLE; heal with scarring and milia formation	Deposition of IgG along the dermal side	No large deposits of mucin in the dermis
Bullous pemphigoid	Prodrome of moderate to severe pruritus +/− urticarial, papular lesions; responsive to corticosteroids	Linear deposition of IgG along epidermal side of split skin	Superficial perivascular inflammatory infiltrate with numerous eosinophils
Linear IgA bullous dermatosis	Drug‐induced; idiopathic	Linear deposition of IgA on the epidermal side of split skin	Resembles dermatitis herpetiformis

4. CONCLUSION

BSLE should be considered in the differential diagnosis of bullous lesions, particularly in patients with established or suspected SLE. The presented case underscores the importance of obtaining a skin biopsy with histopathological and immunofluorescence examinations for accurate diagnosis. Hence, it is imperative for clinicians to be aware of this rare condition.

AUTHOR CONTRIBUTIONS

Samikchhya Keshary Bhandari: Conceptualization; project administration; resources; writing – original draft; writing – review and editing. Naveen Gautam: Resources; writing – original draft. Anupama Pandeya: Resources. Saket Jha: Supervision; writing – review and editing.

FUNDING INFORMATION

There are no funding available for this study.

CONFLICT OF INTEREST STATEMENT

The authors declare there are no potential/perceived conflicts of interest.

ETHICS STATEMENT

No ethical approval is needed in our institute for case report.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Bhandari SK, Gautam N, Pandeya A, Jha S. A case of bullous systemic lupus erythematosus: Diagnostic challenges and clinical implications. Clin Case Rep. 2023;11:e8167. doi: 10.1002/ccr3.8167

DATA AVAILABILITY STATEMENT

Not applicable.