Anti–type VII collagen autoantibodies are often detectable in patients with bullous systemic lupus erythematosus (BSLE). However, the timing of their appearance preceding the onset of disease is unknown to date.
We report the case of a 50-year-old woman with a history of SLE who was seen with vesicles and bullae around her lips, trunk, axillae, arms, and thighs. Histologic analysis and immunofluorescence and immunoblot studies confirmed the diagnosis of BSLE. Immunoblotting and enzyme-linked immunosorbent assay studies of the patient’s serum obtained 3 months before the onset of BSLE showed the presence of anti–type VII collagen autoantibodies. Levels of anti–type VII collagen IgG increased after bullous lesions appeared. Within 1 month after initiating dapsone therapy and increasing the dosage of prednisone, skin lesions promptly resolved. One year after the onset of BSLE, the anti–type VII collagen IgG decreased below levels observed before the inception of the bullous lesions.
Conclusions and Relevance
Anti–type VII collagen autoantibodies can precede the clinical appearance of BSLE. The subsequent increase and decrease in levels of circulating anti–type VII collagen autoantibodies, which mirrored skin disease activity, support a potential role in their initiation of disease.
Bullous systemic lupus erythematosus (BSLE) is a rare vesiculobullous eruption favoring photoexposed areas and mucous membranes. Vesicles and bullae of varying sizes can appear with crusting and resolve as hyperpigmented patches. The absence of milia and scarring, as well as the prominence in trauma-prone areas, distinguishes this entity from epidermolysis bullosa acquisita (EBA). The histology of BSLE primarily shows subepidermal blisters and neutrophilic upper dermal infiltrates; direct immunofluorescence studies of normal-appearing perilesional skin demonstrate immunoglobulin and complement deposition at the basement membrane zone.1
While other antigenic targets, such as bullous pemphigoid antigen 1, laminin-5, and laminin-6, have been reported in BSLE,2 anti–type VII collagen autoantibodies have been detected in the serum of many patients with BSLE.3 As the major component of the anchoring fibrils, type VII collagen links the lamina densa to the underlying dermis.4 Although autoantibodies in the serum of patients with SLE before their diagnosis have been previously observed,5 whether circulating anti–type VII collagen autoantibodies are present before the appearance of BSLE is unknown. We describe a patient with SLE whose serum contained IgG anti–type VII collagen autoantibodies before BSLE onset. Moreover, after the BSLE resolved, the anti–type VII collagen IgG levels diminished below those documented before the onset of the immunobullous disease.
A 50-year-old African American woman with type II diabetes mellitus and a 6-month history of SLE was seen at the University of Texas Southwestern dermatology outpatient clinic. She manifested positive American College of Rheumatology SLE criteria,6 including arthritis, oral ulcers, photosensitivity, discoid lupus erythematosus, positive antinuclear antibody test results, and immunologic disorder (positive anti–Smith antibodies). She had a 3-week history of a pruritic, vesiculobullous eruption covering her perioral area, trunk, axillae, arms, and inner thighs.
At the onset of the eruption, the patient was taking prednisone (7.5 mg daily), which had been tapered from 15 mg daily 1 month previously. She had also been taking chloroquine phosphate (250 mg daily on weekdays and 125 mg daily on weekends) and mycophenolate mofetil (500 mg twice daily) for the past 3 months. In response to the rash and presumed lupus flare due to her arthritis, the elevated double-stranded DNA titers, and her low complement levels, her rheumatologist had increased the prednisone dosage to 30 mg daily. The patient also had discontinued the mycophenolate mofetil and chloroquine herself because she was concerned about drug reactions.
On physical examination, multiple tense vesicles and bullae with hemorrhagic crusting and annular erythematous plaques were observed on her back, chest, abdomen, eyebrows, forearms, upper arms, inner thighs, axillae (Figure 1A), and perioral area (Figure 1B). The patient had diffuse scarring alopecia on her scalp, with hypopigmented patches and underlying erythema on the crown, consistent with discoid lupus erythematosus.
A, Shown are multiple small and large tense vesicles and bullae in the patient’s right axilla. B, Vesicles and bullae with surrounding erythematous plaques with hemorrhagic crusting are seen in the perioral area.
A biopsy specimen from the edge of a bulla on the right upper arm showed a subepidermal vesiculobullous dermatosis with neutrophils, occasional lymphocytes, and red blood cells within the blister cavity and a sparse perivascular infiltrate with lymphocytes and neutrophils (Figure 2A). Direct immunofluorescence showed a linear pattern (Figure 2B) of C3, IgA, and IgG along the basement membrane zone. Indirect immunofluorescence studies of the patient’s serum on salt-split skin (which is normal skin treated with 1M sodium chloride that splits the epidermis and dermis at the basement membrane level) showed positive IgG binding to the dermal side at a titer of 1:10 (Figure 2C).
A, Histologic analysis of a biopsy specimen from the right upper arm shows a subepidermal bulla with separation of the epidermis from the underlying dermis. B, Direct immunofluorescence study shows IgG with a strong linear deposition along the basement membrane zone. C, Indirect immunofluorescence study of serum obtained from the patient during her active disease flare shows IgG at a 1:10 titer binding to the dermal side of 1M salt-split skin. Original magnification ×200.
Immunoblot studies of a recombinant of the noncollagenous (NC1) domain of type VII collagen confirmed that the patient had IgG autoantibodies directed against this signature autoantigen (Figure 3A). After the diagnosis of BSLE was made, the patient was treated with dapsone (50 mg twice daily) and commenced a tapering dose of prednisone, starting at 40 mg daily. One month later, the patient had experienced a significant decrease in vesicles. After 3 months of skin inactivity, the patient’s prednisone was discontinued, and dapsone was discontinued 4 months later. Twelve months after the eruption, the patient had hyperpigmented macules and patches in her perioral area, axillae, trunk, and arms, with no bullae or vesicles.
A, Immunoblot study on a recombinant of the NC1 domain of type VII collagen shows IgG binding to the signature autoantigen (arrow). Lane 1 shows normal control serum. Lane 2 shows the serum of a patient with epidermolysis bullosa acquisita. The serum of the case patient at 1:40 dilution is shown 3 months before eruption (lane 3) and 3 weeks after rash onset (lane 4). B, Indirect immunofluorescence study of the case patient’s serum 3 months before disease onset shows IgG binding to the dermal side of the dermal-epidermal junction in salt-split skin at a 1:5 titer (original magnification ×200).
Three months before her BSLE onset, a serum sample had been collected from the patient, who had been receiving a stable dosage of prednisone (15 mg daily) for 2 months because she had enrolled in the University of Texas Southwestern Cutaneous Lupus Registry, which is a longitudinal observational study of the disease course of patients with cutaneous lupus. Twelve months after her BSLE appeared, another serum sample was drawn from the patient, who had been taking chloroquine phosphate (250 mg daily) for 4 months. Immunofluorescence studies of the serum sample drawn before BSLE onset on salt-split skin showed IgG bound to the dermal side at a titer of 1:5 (Figure 3B). Immunoblot studies of the NC1 type VII collagen recombinant again demonstrated IgG autoantibodies against this particular antigen in the serum samples drawn 3 months before and 3 weeks after the eruption had started (Figure 3A). During the course of the patient’s immunobullous lesions, quantitation of IgG anti–type VII collagen autoantibodies by enzyme-linked immunosorbent assay (MBL International) revealed sequential values of 9.23 U/mL (3 months before disease onset), 71.74 U/mL (3 weeks after disease onset), and 2.30 U/mL (12 months after disease onset).
This case report describes novel findings in a patient with BSLE with anti–type VII collagen autoantibodies in her serum 3 months before the onset of the disease. After these autoantibodies had increased 3 weeks following the development of her eruption, resolution of her rash was accompanied by a subsequent decrease in these autoantibodies.
Found in the lamina densa and the sublamina densa fibrillar area of the dermal-epidermal junction, type VII collagen is composed of 3 α chains containing a central collagenous triple helix and domains in the amino-terminal (NC1) and carboxy-terminal (NC2) ends.7 The immunodominant domains of type VII collagen recognized by IgG autoantibodies from patients with BSLE (and EBA) reside in the NC1 domain.3,8 Passive transfer of purified rabbit anti–type VII collagen IgG in adult nude, Balb/c, and C57BL/6 mice resulted in the formation of skin blisters and erosions.9 Similarly, purified anti–type VII collagen antibodies from the serum of patients with EBA injected in hairless mice showed that these antibodies can induce EBA-like skin lesions.10 Based on our observations that anti–type VII collagen autoantibodies had been present in our patient before and had increased after her bullous lesions appeared, we hypothesize that there is a critical threshold of these antibodies in circulation that is surpassed before the skin eruption occurs in BSLE.
The presence and accumulation of circulating autoantibodies have been previously observed in patients with lupus. A large prospective study5 of 130 military recruits who were followed up before their SLE diagnosis showed that multiple autoantibodies, such as antinuclear antibodies and anti–double-stranded DNA antibodies, were present in their blood years before their diagnosis and the onset of systemic symptoms. Moreover, 58% of patients with SLE showed escalating double-stranded DNA antibody levels leading up to their SLE diagnosis.11 A case for the pathogenic potential of autoantibodies in lupus can be made with neonatal lupus, in which transplacental transfer of Ro, La, and ribonucleoprotein autoantibodies occurs from mother to fetus.12 The disease wanes as these autoantibodies level off or decline.13 Moreover, patients with Sjögren’s syndrome with positive Ro autoantibodies have been observed to later develop subacute cutaneous lupus.14
Using the serum sample repository from the University of Texas Southwestern Cutaneous Lupus Registry, we also measured anti–type VII collagen IgG by enzyme-linked immunosorbent assay in age and sex–matched patients with SLE (n = 13), patients with discoid lupus erythematosus (n = 13), and healthy control subjects (n = 14). All these serum samples had levels of anti–type VII collagen IgG below the established positive threshold. The same samples were lower than those observed in our patient’s serum before and during the BSLE eruption and in the serum samples from 2 patients with EBA serving as positive controls (Table). We were able to confirm findings from a previous study15 that the serum of patients with SLE without BSLE does not contain significant levels of anti–type VII collagen autoantibodies.
Twelve months after the initial eruption, our patient’s serum showed markedly decreased levels of anti–type VII collagen IgG. At that time, the patient’s BSLE was quiescent. A similar finding was previously reported in a patient with Sjögren’s syndrome and SLE overlap with BSLE, whose anti–type VII collagen IgG was undetectable at the time of BSLE remission.16 The rise and fall in levels of anti–type VII collagen autoantibodies during the course of a patient’s BSLE disease imply that they have possible usefulness as biomarkers, which can be used to assess disease activity and guide treatment.
Limitations of this study include the small sample size (with the findings observed in 1 patient) and the limited follow-up period of 1 year. In addition, the use of concurrent immunosuppressant medications may alter autoantibody levels. However, the patient herein was receiving stable dosages of her immunosuppressants before and after her BSLE eruption.
In summary, anti–type VII collagen autoantibodies were detected 3 months before the inception of BSLE in a patient with SLE. Their levels subsequently increased after disease onset and decreased with disease resolution. We hypothesize that surpassing a critical level of anti–type VII collagen autoantibodies may be an important event in the evolution of BSLE. An alternative explanation would be that the patient had nonpathogenic autoantibodies before her BSLE. Epitope spreading may be responsible for the appearance of pathogenic autoantibodies, resulting in epidermal-dermal separation and eventual onset of her BSLE.2,17 Larger prospective studies in patients with BSLE measuring levels of anti–type VII collagen autoantibodies throughout their disease course for an extended time frame would be helpful in determining whether these autoantibodies could be reliable disease markers.
Accepted for Publication: October 15, 2014.
Corresponding Author: Benjamin F. Chong, MD, MSCS, Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9069 (firstname.lastname@example.org).
Published Online: February 11, 2015. doi:10.1001/jamadermatol.2014.4409.
Author Contributions: Mr Grabell and Dr Chong had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Grabell, Yancey, Chong.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Grabell, Chong.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Grabell, Chong.
Obtained funding: Yancey, Chong.
Administrative, technical, or material support: Matthews, Yancey, Chong.
Study supervision: Chong.
Conflict of Interest Disclosures: Dr Chong reported being an investigator for Daavlin Corporation. Dr Yancey reported serving on advisory boards for Stiefel/GlaxoSmithKline and Mary Kay, Inc. No other disclosures were reported.
Funding/Support: This study was supported in part by grant K23AR061441 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the University of Texas Southwestern Medical Center and its affiliated academic and health care centers, the National Center for Research Resources, and the National Institutes of Health.
Additional Contributions: Rose Cannon (Department of Dermatology, University of Texas Southwestern Medical Center) provided administrative support in the preparation of the manuscript.
Grabell DA, Matthews LA, Yancey KB, Chong BF. Detection of Type VII Collagen Autoantibodies Before the Onset of Bullous Systemic Lupus Erythematosus. JAMA Dermatol. 2015;151(5):539-543. doi:10.1001/jamadermatol.2014.4409