Immunologic overlap in a case of linear IgG/IgA bullous dermatosis responsive to rituximab
2021; Elsevier BV; Volume: 9; Linguagem: Inglês
10.1016/j.jdcr.2020.12.029
ISSN2352-5126
AutoresDmitry A. Nedosekin, Kelsey Derrick Wilson, Katelynn Campbell, Sara C. Shalin, Henry K. Wong,
Tópico(s)Urticaria and Related Conditions
ResumoIntroductionAutoimmune subepidermal blistering diseases are caused by immunological loss of tolerance to components of hemidesmosomes, triggering humoral and cellular responses.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar C3 and IgG deposition along the basement membrane zone is characteristic of bullous pemphigoid (BP).1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,2Mihályi L. Kiss M. Dobozy A. Kemény L. Husz S. Clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis.Clin Dev Immunol. 2012; 2012: 369546Crossref PubMed Scopus (7) Google Scholar Alternately, IgA deposition at the basement membrane zone is consistent with linear IgA bullous dermatosis (LABD).1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,3Hashimoto T. Tsuruta D. Koga H. et al.Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University.Br J Dermatol. 2016; 175: 953-965Crossref PubMed Scopus (26) Google Scholar An immunological overlap spanning the clinical and immunologic spectrum between BP and LABD has been reported and referred to as linear IgA/IgG bullous dermatosis (LAGBD).3Hashimoto T. Tsuruta D. Koga H. et al.Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University.Br J Dermatol. 2016; 175: 953-965Crossref PubMed Scopus (26) Google Scholar,4Csorba K. Schmidt S. Florea F. et al.Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases.Orphanet J Rare Dis. 2011; 6: 31Crossref PubMed Scopus (34) Google Scholar LAGBD has a unique clinical presentation, immunologic properties, and distinct therapeutic options1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,5Izaki S. Ito K. Ishii N. Hashimoto T. Fujita H. Terui T. Infantile linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2016; 26: 96-98Crossref PubMed Scopus (5) Google Scholar, 6Wozel G. Blasum C. Dapsone in dermatology and beyond.Arch Dermatol Res. 2014; 306: 103-124Crossref PubMed Scopus (208) Google Scholar, 7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar including rituximab.Case reportA 43-year-old African American man presented with a 7-month history of a worsening erythematous and pruritic rash, which had progressed to blisters and ocular pain 4 weeks prior the presentation. Topical triamcinolone and 2 weeks of 60 mg prednisone had failed to improve the rash. The patient denied any medication changes, history of malignancy, autoimmune disease, or inflammatory bowel disease. Past medical history was significant for end-stage renal disease secondary to hypertension (on hemodialysis) and obstructive sleep apnea. Medications included clonazepam, promethazine, metoprolol, and gabapentin. Physical examination showed numerous erosions with collarettes of scale and tense bullae in "string of pearls" annular configurations on the bilateral arms, thighs, and trunk (Fig 1, A and B). Mucosal involvement included sloughing of the left eye conjunctiva and tongue.Histopathology from skin biopsies with hematoxylin-eosin stain and direct immunofluorescence microscopy was consistent with BP, demonstrating a subepidermal split, an eosinophil-rich inflammatory infiltrate (Fig 2), strong linear C3 deposition, equivocal IgG, and absent IgA along the basement membrane zone. However, indirect immunofluorescence with salt split skin revealed both linear IgG and IgA at the roof of the induced blister (epidermal staining pattern). Enzyme-linked immunosorbent assay was positive for circulating anti-BP180 antibodies in the patient's serum, with IgG and IgA titers of 1:160 and 1:20, respectively. Anti-BP230 antibodies were absent.Fig 2Biopsy specimens obtained from the right posterior shoulder. A, subepidermal blister. No necrosis of keratinocytes noted. B, Mixed inflammatory infiltrate including lymphocytes, histiocytes, and abundant eosinophils extending down to the level of the superficial vascular plexus. (Hematoxylin-eosin stain.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)After an additional 2 weeks of prednisone without improvement, the patient was started on rituximab 375 mg/m2 weekly for 4 weeks and mycophenolate mofetil 500 mg twice daily. Prednisone was increased to 80 mg (0.5 mg/kg body weight). Dapsone was avoided due to anemia; methotrexate was avoided due to end-stage renal disease and morbid obesity. Gabapentin was discontinued due to the possibility of drug-induced BP.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,8Flamm A. Sachdev S. Dufresne F. Gabapentin-induced bullous pemphigoid.J Am Osteopath Assoc. 2017; 117: 191-193Crossref PubMed Scopus (2) Google Scholar Ophthalmology recommended prednisolone acetate ophthalmic suspension, and tobramycin, and dexamethasone ointments. Age-appropriate cancer and autoimmune disease screenings were recommended. Bullae completely cleared after 4 rituximab infusions (Fig 1, C), and prednisone was tapered over a month. The disease relapsed 9 months after initial treatment, but cleared with 2 additional rituximab infusions.DiscussionAutoimmune subepidermal blistering diseases are rare. The BP incidence is 6-13 per million people and typically affects adults over 60 years of age. The LABD incidence is 0.3-2.3 per million and may present both in children and adults.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar A review of 45 LAGBD cases in Japan showed that 49% of the patients were younger than 60 years of age.9Horiguchi Y. Ikoma A. Sakai R. Masatsugu A. Ohta M. Hashimoto T. Linear IgA dermatosis: report of an infantile case and analysis of 213 cases in Japan.J Dermatol. 2008; 35: 737-743Crossref PubMed Scopus (48) Google ScholarIn BP, the most common antigens are BP230 (a 230-kDa intracellular protein) and BP180 (a 180-kDa transmembrane glycoprotein).1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar Antibodies against BP180 are believed to induce the initial blisters, while anti-BP230 antibodies enhance the inflammatory reaction.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,2Mihályi L. Kiss M. Dobozy A. Kemény L. Husz S. Clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis.Clin Dev Immunol. 2012; 2012: 369546Crossref PubMed Scopus (7) Google Scholar In LABD, the target antigens are the 97-kDa or 120-kDa fractions of BP180 carboxy-terminus. In LAGBD, IgG and IgA antibodies target BP180 most commonly,4Csorba K. Schmidt S. Florea F. et al.Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases.Orphanet J Rare Dis. 2011; 6: 31Crossref PubMed Scopus (34) Google Scholar,10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar, 11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar, 12Metz B.J. Ruggeri S.Y. Hsu S. et al.Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype.Int J Dermatol. 2004; 43: 443-446Crossref PubMed Scopus (13) Google Scholar, 13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar, 14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar and, less often, laminin-33211Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,15Li X. Tsuchisaka A. Qian H. et al.Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins.Eur J Dermatol. 2015; 25: 418-423Crossref PubMed Scopus (14) Google Scholar,16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar and BP230.11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar Drug-induced BP and LABD have been reported1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar; there is, however, no specific association of LAGBD with drugs.7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar,10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar, 11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar, 12Metz B.J. Ruggeri S.Y. Hsu S. et al.Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype.Int J Dermatol. 2004; 43: 443-446Crossref PubMed Scopus (13) Google Scholar, 13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar, 14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar, 15Li X. Tsuchisaka A. Qian H. et al.Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins.Eur J Dermatol. 2015; 25: 418-423Crossref PubMed Scopus (14) Google Scholar, 16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar, 17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar, 18Kakugawa T. Tomimura S. Hayashi T. et al.Interstitial pneumonia associated with linear immunoglobulin A/immunoglobulin G bullous dermatosis.Respiration. 2013; 86: 347-351Crossref PubMed Scopus (6) Google Scholar LAGBD has been reported in patients with ulcerative colitis,13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar B-cell lymphoma,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar and colorectal carcinoma.11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google ScholarClinical manifestations of BP and LABD are variable and can overlap. LAGBD presentations include erythema,10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar pustules,14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar tense bullous lesions7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar,10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar, 11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar, 12Metz B.J. Ruggeri S.Y. Hsu S. et al.Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype.Int J Dermatol. 2004; 43: 443-446Crossref PubMed Scopus (13) Google Scholar,16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar and small vesicles in annular patterns.10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar,16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar Ocular and oral mucosa7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar,11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar involvement, as well as a case of LAGBD-related interstitial pneumonia,19Lamberts A. Euverman H.I. Terra J.B. Jonkman M.F. Horváth B. Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases.Front Immunol. 2018; 9: 248Crossref PubMed Scopus (55) Google Scholar have been reported. The relationship between LAGBD clinical manifestations and the type of predominant antibody highlights that BP, LAGBD, and LABD are on a spectrum.20Li Z. Jing K. Li S. Feng S. Antigen recognition in the pathogenesis of immunoglobulin A-related autoimmune bullous diseases.Postepy Dermatol Alergol. 2018; 35: 338-343Crossref PubMed Scopus (1) Google ScholarHistopathologic evaluation shows subepidermal bullae.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar Eosinophilic spongiosis and/or dermal infiltrate of eosinophils are seen in BP. LABD shows predominantly neutrophilic infiltrates.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar LAGBD has mixed eosinophilic and neutrophilic infiltrates.10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar,15Li X. Tsuchisaka A. Qian H. et al.Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins.Eur J Dermatol. 2015; 25: 418-423Crossref PubMed Scopus (14) Google Scholar Direct immunofluorescence typically reveals the presence of linear deposits of IgG, IgA, and C3. LAGBD has been reported to have IgA and IgG binding mostly to the epidermal surface (as seen in this case),10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,12Metz B.J. Ruggeri S.Y. Hsu S. et al.Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype.Int J Dermatol. 2004; 43: 443-446Crossref PubMed Scopus (13) Google Scholar, 13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar, 14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar,21Cozzani E. Drosera M. Parodi A. Carrozzo M. Gandolfo S. Rebora A. Frequency of IgA antibodies in pemphigus, bullous pemphigoid and mucous membrane pemphigoid.Acta Derm Venereol. 2004; 84: 381-384Crossref PubMed Scopus (25) Google Scholar and rarely combined epidermal-dermal11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,15Li X. Tsuchisaka A. Qian H. et al.Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins.Eur J Dermatol. 2015; 25: 418-423Crossref PubMed Scopus (14) Google Scholar or dermal16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar sides.Treatment starts with a review of medications to identify and discontinue drugs potentially inducing the disease.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,8Flamm A. Sachdev S. Dufresne F. Gabapentin-induced bullous pemphigoid.J Am Osteopath Assoc. 2017; 117: 191-193Crossref PubMed Scopus (2) Google Scholar Age-appropriate screening for malignancy may be appropriate.11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar Systemic and topical corticosteroids are first-line treatment1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,2Mihályi L. Kiss M. Dobozy A. Kemény L. Husz S. Clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis.Clin Dev Immunol. 2012; 2012: 369546Crossref PubMed Scopus (7) Google Scholar; however, significant side effects are common. Dapsone treatment is an effective option in LAGBD, limiting systemic immunosuppression.2Mihályi L. Kiss M. Dobozy A. Kemény L. Husz S. Clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis.Clin Dev Immunol. 2012; 2012: 369546Crossref PubMed Scopus (7) Google Scholar,7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar,13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar,16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar Dapsone inhibits neutrophil adhesion and release of tissue-damaging oxidants and proteases.6Wozel G. Blasum C. Dapsone in dermatology and beyond.Arch Dermatol Res. 2014; 306: 103-124Crossref PubMed Scopus (208) Google Scholar Side effects include hemolytic anemia, methemoglobinemia, neutropenia, neuropathy, and hepatitis. It is contraindicated for patients with anemia (as in our case), liver disease, or low glucose-6-phosphate dehydrogenase enzyme levels.6Wozel G. Blasum C. Dapsone in dermatology and beyond.Arch Dermatol Res. 2014; 306: 103-124Crossref PubMed Scopus (208) Google ScholarSteroid-sparing adjunctive therapies include azathioprine, mycophenolate mofetil, intravenous immunoglobulin,1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar and targeted therapies such as rituximab, an anti-CD20 monoclonal antibody. Rituximab is Food and Drug Administration-approved for the treatment of pemphigus vulgaris. Case reports describe rituximab use for both BP and LABD with higher efficacy observed in IgG-dominant disease.19Lamberts A. Euverman H.I. Terra J.B. Jonkman M.F. Horváth B. Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases.Front Immunol. 2018; 9: 248Crossref PubMed Scopus (55) Google Scholar In BP, rituximab has a reported complete response rate of 85%, a recurrence rate of 29%, and an adverse effects rate of 24%.22Kremer N. Snast I. Cohen E.S. et al.Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review of the literature.Am J Clin Dermatol. 2019; 20: 209-216Crossref PubMed Scopus (56) Google Scholar Side effects include infections, anemia, syndrome of inappropriate antidiuretic hormone secretion, drug fever, acute pruritus, peripheral arterial occlusive disease, and tachycardia.22Kremer N. Snast I. Cohen E.S. et al.Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review of the literature.Am J Clin Dermatol. 2019; 20: 209-216Crossref PubMed Scopus (56) Google Scholar Rituximab is an important treatment option for patients with multiple medical co-morbidities and severe disease as presented in this case report.The case presented here highlights the importance of distinguishing between BP, LABD, and LAGBD (Table I). The young age of the patient, mucosal involvement, and bullae in an annular configuration were not typical for classic BP. Only by further evaluation with indirect immunofluorescence and enzyme-linked immunosorbent assay were IgA antibodies identified. The LAGBD diagnosis allows treatment with dapsone (not readily used for BP) or rituximab in severe cases. Due to distinct clinical features, immunologic findings, and treatment modalities, it is important for LAGBD to be recognized as a subtype of subepidermal blistering disease.Table IComparison of clinical, histological, and immunological findings in BP, LAGBD, and LABDBullous pemphigoid (BP)Linear IgA/IgG bullous dermatosis (LAGBD)Linear IgA bullous dermatosis (LABD)Epidemiology•6-13 cases per million•Onset over 60 years of age•Mean presentation age, 80 years•6.7% of the patients 0-15 years of age•42.3% 15-60 years of age•51% >60 years9Horiguchi Y. Ikoma A. Sakai R. Masatsugu A. Ohta M. Hashimoto T. Linear IgA dermatosis: report of an infantile case and analysis of 213 cases in Japan.J Dermatol. 2008; 35: 737-743Crossref PubMed Scopus (48) Google Scholar•0.3-2.3 cases per million•Childhood disease with mean age of 4.5 years; adult disease onset >60 yearsAssociated conditions/triggers•Medications•Autoimmune diseases•Neurological diseases•Trauma, burns, UV radiation•Gastrointestinal diseases13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar•Malignancy11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar•Medications•Autoimmune diseases•Gastrointestinal diseases•Malignancy•InfectionsPathogenesis (autoantibodies)•BP180•BP230•BP1804Csorba K. Schmidt S. Florea F. et al.Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases.Orphanet J Rare Dis. 2011; 6: 31Crossref PubMed Scopus (34) Google Scholar,10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar, 11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar, 12Metz B.J. Ruggeri S.Y. Hsu S. et al.Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype.Int J Dermatol. 2004; 43: 443-446Crossref PubMed Scopus (13) Google Scholar, 13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar, 14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar•BP23011Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar•Laminin-33211Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,15Li X. Tsuchisaka A. Qian H. et al.Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins.Eur J Dermatol. 2015; 25: 418-423Crossref PubMed Scopus (14) Google Scholar,16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar•97-kDa and 120-kDa fraction of BP180•BP180•BP230•Anti-Type VII collagenClinical presentation•Pruritus•Tense blisters and vesicles•Erosions and crusting•Urticarial and infiltrated papules and plaques•Oral involvement in 10%-30%•Eye, nose, pharynx, esophagus, and anogenital involvement is rare•Pruritus•Tense blisters and vesicles•Annular vesicular pattern10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar,16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar•Erosions and crusting•Erythema•Ocular and oral mucosa involvement7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar,11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar•Pruritus•Tense blisters and vesicles•Annular or hepetiform vesicular pattern•Erosions and crusting•Oral, ocular, nasal, pharyngeal, and esophageal involvement in up to 80% of patientsSubepidermal blistersPathology findingsEosinophilic and mononuclear cell infiltrateMixed eosinophilic and neutrophilic infiltrate10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,11Sakaguchi M. Bito T. Oda Y. et al.Three cases of linear IgA/IgG bullous dermatosis showing IgA and IgG reactivity with multiple antigens, particularly laminin-332.JAMA Dermatol. 2013; 149: 1308-1313Crossref PubMed Scopus (26) Google Scholar,13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar,15Li X. Tsuchisaka A. Qian H. et al.Linear IgA/IgG bullous dermatosis reacts with multiple laminins and integrins.Eur J Dermatol. 2015; 25: 418-423Crossref PubMed Scopus (14) Google ScholarNeutrophilic infiltrateDirect immunofluorescenceIgG and/or C3IgG + IgA and/or C3IgA and/or C3Indirect immunofluorescence•IgG•Mainly epidermal pattern•Combined epidermal/dermal pattern•IgG and IgA•Mainly epidermal pattern10Inamura E. Nishie W. Yamaguchi Y. et al.Linear IgA/IgG bullous dermatosis with autoantibodies directing the native and processed forms of BP180.Br J Dermatol. 2020; 182: 1061-1062Crossref PubMed Scopus (2) Google Scholar,12Metz B.J. Ruggeri S.Y. Hsu S. et al.Linear IgA dermatosis with IgA and IgG autoantibodies to the 180 kDa bullous pemphigoid antigen (BP180): evidence for a distinct subtype.Int J Dermatol. 2004; 43: 443-446Crossref PubMed Scopus (13) Google Scholar, 13Onoe A. Matsuura D. Terui T. Ishii N. Hashimoto T. Ochiai T. Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis.J Dermatol. 2017; 44: 1295-1298Crossref PubMed Scopus (7) Google Scholar, 14Matsumoto T. Nakamura S. Ishii N. et al.Erythrodermic linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2019; 29: 220-221PubMed Google Scholar,17Morita K. Fuijisawa A. Yagi Y. et al.Immunoglobulin A anti-BP230 autoantibodies in linear immunoglobulin A/immunoglobulin G bullous dermatosis.J Dermatol. 2011; 38: 1030-1032Crossref PubMed Scopus (3) Google Scholar,21Cozzani E. Drosera M. Parodi A. Carrozzo M. Gandolfo S. Rebora A. Frequency of IgA antibodies in pemphigus, bullous pemphigoid and mucous membrane pemphigoid.Acta Derm Venereol. 2004; 84: 381-384Crossref PubMed Scopus (25) Google Scholar•Combined epidermal/dermal pattern16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar•Rarely dermal pattern16Izaki S. Mitsuya J. Okada T. Koga H. Hashimoto T. Terui T. A case of linear IgA/IgG bullous dermatosis with anti-laminin-332 autoantibodies.Acta Derm Venereol. 2015; 95: 359-360Crossref PubMed Scopus (7) Google Scholar•IgA•Mainly epidermal pattern•Combined epidermal/dermal pattern•Rarely dermal pattern9Horiguchi Y. Ikoma A. Sakai R. Masatsugu A. Ohta M. Hashimoto T. Linear IgA dermatosis: report of an infantile case and analysis of 213 cases in Japan.J Dermatol. 2008; 35: 737-743Crossref PubMed Scopus (48) Google ScholarBP, Bullous pemphigoid; LAGBD, linear IgA/IgG bullous dermatosis; LABD, linear IgA bullous dermatosis. Open table in a new tab IntroductionAutoimmune subepidermal blistering diseases are caused by immunological loss of tolerance to components of hemidesmosomes, triggering humoral and cellular responses.1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar C3 and IgG deposition along the basement membrane zone is characteristic of bullous pemphigoid (BP).1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,2Mihályi L. Kiss M. Dobozy A. Kemény L. Husz S. Clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis.Clin Dev Immunol. 2012; 2012: 369546Crossref PubMed Scopus (7) Google Scholar Alternately, IgA deposition at the basement membrane zone is consistent with linear IgA bullous dermatosis (LABD).1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,3Hashimoto T. Tsuruta D. Koga H. et al.Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University.Br J Dermatol. 2016; 175: 953-965Crossref PubMed Scopus (26) Google Scholar An immunological overlap spanning the clinical and immunologic spectrum between BP and LABD has been reported and referred to as linear IgA/IgG bullous dermatosis (LAGBD).3Hashimoto T. Tsuruta D. Koga H. et al.Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University.Br J Dermatol. 2016; 175: 953-965Crossref PubMed Scopus (26) Google Scholar,4Csorba K. Schmidt S. Florea F. et al.Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases.Orphanet J Rare Dis. 2011; 6: 31Crossref PubMed Scopus (34) Google Scholar LAGBD has a unique clinical presentation, immunologic properties, and distinct therapeutic options1Bolognia J. Schaffer J.V. Cerroni L. Dermatology.4th ed. Elsevier, China2018Google Scholar,5Izaki S. Ito K. Ishii N. Hashimoto T. Fujita H. Terui T. Infantile linear IgA/IgG bullous dermatosis.Eur J Dermatol. 2016; 26: 96-98Crossref PubMed Scopus (5) Google Scholar, 6Wozel G. Blasum C. Dapsone in dermatology and beyond.Arch Dermatol Res. 2014; 306: 103-124Crossref PubMed Scopus (208) Google Scholar, 7Passos L. Rabelo R.F. Matsuo C. Santos M. Talhari S. Talhari C. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.An Bras Dermatol. 2011; 86: 747-750Crossref PubMed Scopus (7) Google Scholar including rituximab.
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