Linear IgA Bullous Dermatosis A Rare Clinicopathologic Entity with an Unusual Presentation

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aSoham Chaudhari, DO; bNarciss Mobini, MD aPalisades Medical Center, North Bergen, New Jersey; bUniversity of Nevada School of Medicine, Reno and Las Vegas, Nevada; Associated Pathologists, Chartered, Las Vegas, Nevada

Disclosure: The authors report no relevant conflicts of interest.


Abstract

Linear immunoglobulin A bullous dermatosis is a rare autoimmune mucocutaneous disorder caused by immunoglobulin A autoantibodies produced against several different antigens in the basement membrane zone. Clinically, it is characterized by tense vesicles or bullae, which on histopathological exam demonstrate subepidermal blister with a predominantly neutrophilic infiltrate. A smooth, linear pattern of immunoglobulin A deposition in the basement membrane zone on direct immunofluorescence is considered the gold standard for establishing a diagnosis. Treatment consists of dapsone or sulfapyridine. The authors report a 60-year-old woman who presented with pruritic erythematous patches and plaques on her trunk, back, and legs without blisters, who was diagnosed with eczema for several months with no response to prior treatments. A biopsy was performed, which was consistent with linear immunoglobulin A bullous dermatosis and later confirmed by direct immunofluorescence studies. The authors present this case to increase awareness of this rare disease, which could manifest in a nonclassical, nonblistering fashion. (J Clin Aesthet Dermatol. 2015;8(10):43–46.)


 

Linear immunoglobulin A (IgA) bullous dermatosis (LABD), also known in the literature as linear IgA dermatosis, linear IgA disease, IgA pemphigoid, and linear dermatitis herpetiformis, was first described by Bowen in 1901; however, it was not recognized as a distinct entity from dermatitis herpetiformis (DH) until 1979. LABD is a rare autoimmune vesiculobullous disease with an incidence of 0.2 to 2.3 cases per million-population per year. Epidemiologically, there is an unestablished predominance of race or sex.[1],[2]

LABD has two clinical variants. In children, the disease is better known as chronic bullous disease of childhood (CBDC) with an average presentation occurring around 4.5 years.[3] In adults, two peaks are identified—teenage years and the sixties.1

Case Report

A 60-year-old woman presented with a history of pruritic lesions on her trunk, back, and legs for several months. She had received multiple treatments for what was believed to be an eczematous dermatitis with no benefits. Physical examination revealed erythematous and focally urticarial patches and plaques with excoriations. No scaling, vesicles, or bullae were found (<a title=”Figure 1″href=”https://bwcbuildout.com/jcad/wp-content/uploads/Mobini-Figure-1.jpg”>Figure 1</a>). The clinical differential diagnosis included dermatitis, not otherwise specified (NOS), urticarial dermatitis, and urticarial vasculitis and a biopsy was performed. Histopathological examination revealed a prominent infiltrate of neutrophils arranged in a linear fashion at the dermoepidermal junction, where there was prominent vacuolar alteration of basal layer keratinocytes, associated with individually necrotic cells (<a title=”Figure 2″href=”https://bwcbuildout.com/jcad/wp-content/uploads/Mobini-Figure-2.jpg”>Figure 2</a and<a title=”Figure 3″href=”https://bwcbuildout.com/jcad/wp-content/uploads/Mobini-Figure-3.jpg”>Figure 3</a>). The diagnosis of vacuolar interface dermatitis, neutrophil predominant (aligned in linear array) was rendered. The histopathological differential diagnosis included linear IgA dermatosis (LAD) with atypical presentation, unusual interface drug reaction, neutrophil-rich bullous pemphigoid (BP), unusual DH, and systemic erythematous lupus (SLE). Based on the findings, a direct immunofluorescence (DIF) study was recommended for confirmation, which revealed linear deposition of IgA at dermo-epidermal junction (DEJ) consistent with LAD. The patient was then successfully treated with dapsone.

Discussion

Epidemiologically, LAD is a rare immunobullous disease with an incidence of 0.2 to 2.3 cases per million per year. Clinically, two types exist. In children, during the first decade of life, individual lesions are arranged in an annular pattern called “cluster of jewels” or “string of pearls” as new blisters begin to appear at the periphery of the crusted old bullae. The teenage years and sixth decade of life are the other two peaks of presentation, where pruritic papules with tense vesicles and bullae on an erythematous base appear. The bullae can rupture due to intense itching and resolve as crusts and erosions. LABD lesions typically have a widespread distribution, most notably on the thighs, buttocks, lower trunk, genital region, scalp, and face. Mucosal lesions occur in the oral cavity, conjunctiva, nose, genitalia, pharynx, larynx, anus, and esophagus.[1],[3–6] Of these, oral and ocular are the most commonly involved.[1],[3] LABD has a heterogeneous clinical presentation. The clinical differential diagnosis includes dermatitis herpetiformis (DH) and BP among others. DH presents as grouped (“herpetiform”) vesicles on the scalp, extensor extremities, or sacral region. Oral mucosal involvement is rare, unlike LABD. Histopathological findings demonstrate neutrophilic microabscesses at the dermal papillae and not as linear arrangement at the DEJ. DIF demonstrates granular deposits of IgA within the papillary dermis, not a linear pattern as seen in LABD. The mechanism for LABD is considered to be similar to DH, wherein complement activation and neutrophil chemotaxis is initiated by IgA deposits. BP manifests clinically as pruritic plaques, bullae, and erosions with mucosal involvement. It usually affects the older age group. Histologically, BP shows subepidermal blisters with increased eosinophils and DIF reveals linear IgG and C3 depositions along the basement membrane zone (BMZ). Other conditions in the differential diagnosis list may include bullous impetigo and epidermolysis bullosa acquisita. Bullous impetigo, caused by Staphylococcus aureus infection, is most commonly seen in children, with easily ruptured intraepidermal bullae and oozing fluid on face, trunk, or extremities, which can become dried and crusty. Epidermolysis bullosa acquisita (EBA) can be distinguished from LABD due to IgG deposits at the BMZ on DIF. Although purely IgA-mediated EBA has been described, other clinical characteristics, such as milia and atrophic scarring, can be used to differentiate it from LABD. Rarely, LABD can also resemble prurigo nodularis, morbilliform drug eruptions, erythema multiforme, toxic epidermal necrolysis, annular-polycyclic (EAC-like), seborrheic dermatitis-like, and urticarial.[7–11]

On histopathological examination, there is a subepidermal blister with neutrophil-predominant infiltrate in the superficial dermis and predominantly at the DEJ, characteristically arranged in a linear array. The most preferred site for a biopsy is the back. Biopsies from the forearm do not usually yield positive results.[5],[12] The gold standard for establishing a diagnosis of LABD is DIF. In DIF, there are linear deposits of IgA along the basement membrane at the DEJ. There may also rarely be coexistence of IgG, IgM, and C3.3 DH can rarely demonstrate a similar pattern, although a granular pattern is more typical along with gluten-sensitive enteropathy. Indirect immunofluorescence (IIF) is used to detect circulating IgA antibodies. There is a higher frequency of circulating autoantibodies in CBDC than in LABD.3 IIF has shown that the majority of patients have a purely epidermal side binding of the antibodies using salt-split skin specimens, although some purely dermal and a few mixed patterns can also be noted.[13] Western immunoblotting is a more sensitive method than IIF, and the most frequently detected antigens are the BP180, LABD-97, and Ladinin-1 (LAD-1). On immunoelectron microscopy, IgA is detected at lamina lucida, lamina densa/sublamina densa, or both.

LABD has been reported in association with systemic diseases, such as autoimmune diseases like ulcerative colitis, Crohn’s disease, rheumatoid arthritis, psoriasis, and SLE.[14–19] Interestingly, pregnancy was found to have ameliorated LABD clinically, due to glycosylation of IgA by the increased estrogens and prolactin, thereby causing a conformational change and altering its ability to bind to antigens.[20]

While most cases of LABD are idiopathic, it can be induced by several drugs, mostly vancomycin.[21] Nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, cephalosporins, and angiotensin-converting-enzyme (ACE) inhibitors are also common culprits. The exact pathogenesis of these drugs triggering LABD is not confirmed at this time. Symptoms are noted within one month of drug initiation and withdrawal of the offending agent does cause remission within several weeks.[22–24]

Significant genetic associations between LABD and human leukocyte antigen (HLA) B8, HLA DR3, HLA DQ2, HLA Cw7 have been reported. These haplotypes are common in Caucasians. Possession of the first three of these haplotypes increases susceptibility to an early onset of the disease and are therefore seen more commonly in CBDC. Tumor necrosis factor-2 (TNF-2) gene has been also found to have a significant association with LABD. It represents an unfavorable prognostic factor with an increase in duration of the disease in both children and adults, although more marked in children. On the other hand, TNF-1 allele has been reported to be associated with a shorter disease duration and more favorable prognosis.[25]

The exact pathophysiologic mechanism behind the autoimmune response in LABD remains a topic of continuous investigation, although both a humoral and cellular immune response are involved, which lead to complement activation, inflammatory cell response, and proteolysis. It has been well-established that the IgA antibodies involved in LABD are of the A1 subclass.[26] The target for these antibodies are components of the DEJ adhesion complex, most commonly a 97 kDa (LABD-97) antigen and a 120 kDa (LAD-1) antigen in the lamina lucida. These antigens are fragments of BP180/collagen XVII, a hemidesmosomal type II transmembrane protein that is a key structural component involved in epidermal-dermal adhesion.[4],[27] Its intracellular globular domain is the site of interaction between its NH2 terminal and the NH2 terminal of BPAg1 (BP230) and other hemidesmosomal components. The long, extracellular, rod-shaped collagenous domain of BP180 with noncollagenous domains interspersed, crosses the lamina lucida and the carboxyl terminal colocalizes with laminin 5 in the anchoring filament zone embedding between the lamina lucida and the lamina densa.[1],[4],[5] The full length transmembrane protein form of BP180 is proteolyzed and shed from the cell surface via a furin-dependent process into a soluble 120 kDa ectodomain. The 97 kDa antigen is a proteolytic fragment of the 120 kDa antigen.[28] The shedding of the ectodomain gives rise to new epitopes in collagen XVII through the induction of conformational changes.[4],[5] The NC16A domain of collagen XVII is a common target for IgA antibodies in LABD.1,5 The intracellular BP230 antigen as the major autoantigen in BP is also a target in adult LABD.[5] Other unique antigens that have been found are LAD285 and collagen VII. Collagen VII is seen in 10 to 25 percent of cases of LABD and is the same antigen as seen in EBA. However, in EBA, the autoantigen is of the IgG group and therefore, in LABD the presence of this antigen allows for the nomenclature of “IgA EBA” as seen in our case. Lymphocytes, neutrophils, and eosinophils are involved in the immune response for LABD. CD4+ T helper cells are the predominant lymphocytes recruited. Blisters form due to tissue injury secondary to a localized inflammatory response involving neutrophils, mast cell degranulation, and proteolytic enzymes released in the process.[1] Plasminogen, a proenzyme produced by the liver, is cleaved to its active form plasmin by urokinase-type plasminogen activator or tissue-type. The urokinase-type is found abundantly in normal human skin and is produced by keratinocytes, whereas the tissue-type is found in the skin of individuals with various mucocutaneous disorders.[29] Plasmin is then able to produce the 97-kDa fragment involved in LAD by cleaving type XVII collagen.[30] Plasmin also activates promatrix metalloproteinase 9 (pro-MMP-9) into MMP-9/gelatinase B, which then cleaves and inactivates alpha1-proteinase inhibitor (a1-PI), whose role is to inhibit neutrophil elastase. Hence, neutrophil elastase is uninhibited and contributes to the epidermal-dermal detachment.[31] Furthermore, a1-PI serves as a chemoattractant for neutrophils once it is cleaved and further adds to the tissue damage.[32]

The first-line treatment for LABD is dapsone, an immunomodulatory sulfone.[1],[4],[14],[27],[33] Prior to initiation of dapsone therapy, screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency should be performed and if positive, therapy should be avoided due to risk of hemolytic anemia. In patients who do not have this deficiency, dapsone can still cause methemoglobinemia or a benign hemolysis, which manifests itself as a corrective compensatory reticulocytosis.[4] Such patients may benefit from sulfapyridine or sulfamethoxypyridazine, sulfonamide agents that share structural similarities with dapsone.[4] Currently, the practice of prescribing sulfapyridine has been replaced with sulfasalazine, an inactive form that is degraded by colonic bacteria into 5-aminosalicyclic acid and sulfapyridine. Similar precautions must be taken when prescribing sulfonamides. If these methods fail to control the disease, corticosteroids and/or other immunosuppressive agents can be used. Some antimicrobials have also been found to be highly effective.[1] The last resort to control LABD involves immunoadsorption and intravenous immunoglobulin therapy.[1]

Conclusion

This case emphasizes the significance of maintaining a high index of suspicion when encountering any pruritic, urticarial-like dermatitis that has no bullous component and is resistant to topical treatments, and to include LABD in the differential diagnosis. As this rare disease can present in such a heterogenous and nonclassical fashion, performing a biopsy is crucial in arriving at an accurate diagnosis and subsequent treatment.

References

1. Fortuna G, Marinkovich MP. Linear immunoglobulin A bullous dermatosis. Clin Dermatol. 2012;30(1):38–50.

2. Mintz EM, Morel KD. Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood. Dermatol Clin. 2011;29(3):459–462, ix.

3. Wojnarowska F, Marsden RA, Bhogal B, Black MM. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol. 1988;19(5 Pt 1):792–805.

4. Guide SV, Marinkovich KD. Linear IgA bullous dermatosis. Clin Dermatol. 2001;19(6):719–727.

5. Venning VA. Linear IgA disease: clinical presentation, diagnosis, and pathogenesis. Immunol Allergy Clin North Am. 2012;32(2):245–253, vi.

6. Gluth MB, Witman PM, Thompson DM. Upper aerodigestive tract complications in a neonate with linear IgA bullous dermatosis. Int J Pediatr Otorhinolaryngol. 2004;68(7): 965–970.

7. Torchia D, Caproni M, Del Bianco E, et al. Linear IgA disease presenting as prurigo nodularis. Br J Dermatol. 2006;155(2):479–480.

8. Waldman MA, Black DR, Callen JP. Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol. 2004;29(6):633–636.

9. Billet SE, Kortuem KR, Gibson LE, et al. A morbilliform variant of vancomycin-induced linear IgA bullous dermatosis. Arch Dermatol. 2008;144(6): 774–778.

10. Armstrong AW, Fazeli A, Yeh SW, et al. Vancomycin-induced linear IgA disease manifesting as bullous erythema multiforme. J Cutan Pathol. 2004;31(5):393–397.

11. Khan I, Hughes R, Curran S, et al. Drug-associated linear IgA disease mimicking toxic epidermal necrolysis. Clin Exp Dermatol. 2009;34(6):715–717.

12. Collier PM, Wojnarowska F, Millard PR. Variation in the deposition of the antibodies at different anatomical sites in linear IgA disease of adults and chronic bullous disease of childhood. Br J Dermatol. 1992;127(5):482–484.

13. Wojnarowska F, Collier PM, Allen J, et al. The localization of the target antigens and antibodies in linear IgA disease is heterogeneous, and dependent on the methods used. Br J Dermatol. 1995;132(5):750–757.

14. Horiguchi Y, Ikoma A, Sakai R, et al. Linear IgA dermatosis: report of an infantile case and analysis of 213 cases in Japan. J Dermatol. 2008;35(11):737–743.

15. Taniguchi T, Makino M, Jinnin K, et al. Case of linear IgA bullous dermatosis-involved ulcerative colitis. Inflamm Bowel Dis. 2009;15(9):1284–1285.

16. Paige DG, Leonard JN, Wojnarowska F, et al. Linear IgA disease and ulcerative colitis. Br J Dermatol. 1997;136(5):779–782.

17. Cooke N, Jenkinson H, Wojnarowska F, et al. Coexistence of psoriasis and linear IgA disease in a patient with recent herpes zoster infection. Clin Exp Dermatol. 2005;30(6):643–645.

18. Takagi Y, et al. Coexistence of psoriasis and linear IgA bullous dermatosis. Br J Dermatol. 2000;142(3):513–516.

19. Tobon GJ, Toro CE, Bravo JC, et al. Linear IgA bullous dermatosis associated with systemic lupus erythematosus: a case report. Clin Rheumatol. 2008;27(3):391–393.

20. Collier PM, Kelly SE, Wojnarowska F. Linear IgA disease and pregnancy. J Am Acad Dermatol. 1994;30(3):407–411.

21. Fortuna G, et al. A critical reappraisal of the current data on drug-induced linear immunoglobulin A bullous dermatosis: a real and separate nosological entity? J Am Acad Dermatol. 2012;66(6):988–994.

22. Ho JC, et al. Childhood linear IgA bullous disease triggered by amoxicillin-clavulanic acid. Pediatr Dermatol. 2007;24(5): E40–E43.

23. Nousari HC, Costarangos C, Anhalt GJ. Vancomycin-associated linear IgA bullous dermatosis. Ann Intern Med. 1998;129(6):507–508.

24. Navi D, Michael DJ, Fazel N. Drug-induced linear IgA bullous dermatosis. Dermatol Online J. 2006;12(5):12.

25. Collier PM, Wojnarowska F, Welsh K, et al. Adult linear IgA disease and chronic bullous disease of childhood: the association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis factor influences disease expression. Br J Dermatol. 1999;141(5):867–875.

26. Egan CA, Martineau MR, Taylor TB, et al. IgA antibodies recognizing LABD97 are predominantly IgA1 subclass. Acta Derm Venereol. 1999;79(5):343–346.

27. Chorzelski TP, Jablonska S, Maciejowska E. Linear IgA bullous dermatosis of adults. Clin Dermatol. 1991;9(3): 383–392.

28. Schacke H, et al. Two forms of collagen XVII in keratinocytes. A full-length transmembrane protein and a soluble ectodomain. J Biol Chem. 1998;273(40):25937–25943.

29. Baird J, et al. mRNA for tissue-type plasminogen activator is present in lesional epidermis from patients with psoriasis, pemphigus, or bullous pemphigoid, but is not detected in normal epidermis. J Invest Dermatol. 1990;95(5):548–552.

30. Hofmann SC, et al. Plasmin plays a role in the in vitro generation of the linear IgA dermatosis antigen LADB97. J Invest Dermatol. 2009;129(7):1730–1739.

31. Liu Z, et al. The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell. 2000;102(5):647–655.

32. Banda MJ, et al. The inhibitory complex of human alpha 1-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant. J Exp Med. 1988;167(5):1608–1615.

33. Wojnarowska F. Linear IgA dapsone responsive bullous dermatosis. J R Soc Med. 1980;73(5):371–373.

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Recent Articles:

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