BJD
British Journal of Dermatology
CASE REPORT
A case of vancomycin-associated linear IgA bullous dermatosis and IgA antibodies to the a3 subunit of laminin-332 Y. Zenke,1 T. Nakano,1 H. Eto,1 H. Koga2 and T. Hashimoto2 1 2
Department of Dermatology, St Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan Department of Dermatology, Kurume University School of Medicine, and Institute of Cutaneous Cell Biology, Kurume, Fukuoka, Japan
Summary Correspondence Yukari Zenke. E-mail: [email protected]
Accepted for publication 2 November 2013
Funding sources None.
Conflicts of interest None declared. DOI 10.1111/bjd.12720
Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disease, which is defined by the histopathological finding of subepidermal vesicles with neutrophilic infiltration and linear IgA deposits in the basement membrane zone, revealed by immunofluorescence study. We present a case of LABD in which vancomycin (VCM) administration triggered LABD, and immunoblot analysis showed IgA antibodies reactive to the 145- and 165-kDa a3 subunits of laminin332. This is the first report of VCM-associated LABD in which the target antigen was laminin-332. In the present case, we were compelled to continue administration of VCM along with systemic steroids, which eventually led to the attenuation of the symptoms, normalization of the serum IgA level, and negative results on both indirect immunofluorescence of 1 mol L 1 NaCl-split skin and immunoblot analysis.
What’s already known about this topic?
•
Vancomycin-induced linear IgA bullous dermatosis (LABD) comprises 46% of drug-induced LABD cases and involves reactivity to 83-, 130-, 180-, 230- and 285-kDa proteins.
What does this study add?
• •
We present the first case of vancomycin-associated LABD with IgA antibodies to the a3 subunit of laminin-332. The results of serum IgA level measurement, indirect immunofluorescence and immunoblot analysis were useful to determine the treatment.
Linear IgA bullous dermatosis (LABD) is clinically characterized by the appearance of multiple small itchy bullae within annular erythema on the entire body; the immunological characteristic is linear deposits of IgA on the basement membrane zone (BMZ). Drugs known to induce LABD include captopril, trimethoprim with sulfamethoxazole, phenytoin and diclofenac. Vancomycin (VCM)-induced LABD (VILABD) was first reported in 1988 by Baden et al.;1 thereafter, VCM has been reported as the most common cause of drug-induced LABD, accounting for 462% of cases.2 Immunoblot analysis has been performed in only five cases of VILABD reported previously. This report is the first to present a case of VCM-associated © 2013 British Association of Dermatologists
LABD with evidence of IgA antibodies to the 145- and 165kDa a3 subunits of laminin-332.
Case report A 62-year-old Japanese man, who was treated for brain-stem haemorrhage and diabetes at another hospital, developed infective endocarditis and was transferred to the internal medicine department at our hospital. VCM treatment had started 2 days before admission to our hospital. According to his previous medical record, there was no history of VCM therapy. Rifampicin, sulfamethoxazole with trimethoprim, tazobactam British Journal of Dermatology (2014) 170, pp965–969
965
966 Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al.
with piperacillin and other drugs were administered after hospitalization at our hospital. Ten days after the initiation of intravenous VCM 500 mg per day, oedematous erythema appeared on the trunk. Twelve days later, small-to-mediumsized tense bullae and erosions appeared on the axillae, chest, thighs and buttocks (Fig. 1a). No mucosal lesions were noted and the Nikolsky sign was negative. The blood trough level of VCM at the onset of the erythema was 168 lg mL 1 (normal range 10–20 lg mL 1), and the serum IgA level was 633 mg dL 1 (normal range 110– 410 mg dL 1). The results of IgG enzyme-linked immunosorbent assays for circulating antibodies to BP180 and BP230 were negative. Meticillin-resistant Staphylococcus aureus was detected by blood culture. Initially, we suspected drug eruption, and therefore we discontinued all the drugs other than VCM. VCM was continued because the infectious endocarditis and sepsis had not yet been adequately controlled. Subsequently, intravenous methylprednisolone (60 mg per day) was administered for the first 3 days.
(a)
(b)
However, tense bullae continued to develop on the scrotum and extremities (Fig. 1b); therefore, we restarted methylprednisolone therapy 8 days after the completion of the previous course. VILABD was suspected, and a skin biopsy sample was obtained from a bulla on the abdomen 12 days after hospitalization. Histopathological examination of the sample revealed formation of subepidermal bullae, as well as infiltration of lymphocytes and neutrophils in the upper dermis (Fig. 1c). Direct immunofluorescence of the skin biopsy revealed linear IgA deposits on the BMZ (Fig. 1d). IgG was minimally positive to the BMZ. Both patch test and a drug-induced lymphocyte stimulation test for VCM were performed approximately 1 month after disappearance of the skin lesions and showed negative results. Although VCM was continued, systemic prednisolone suppressed the skin lesions and they reduced gradually. The skin lesions disappeared 45 days after admission, while VCM was still being continued. There was no recurrence and the serum IgA level normalized to 397 mg dL 1 (Fig. 2).
(c)
(d) Fig 1. Clinical manifestations 12 days after the initiation of vancomycin (a) and after the initiation of prednisolone (b). (c) Histopathological findings of skin biopsy (2009, haematoxylin and eosin staining). (d) Direct immunofluorescence for IgA.
Fig 2. Time graph with data on medication, disease activity (blistering) and blood sampling. mPSL, methylprednisolone; VCM, vancomycin. British Journal of Dermatology (2014) 170, pp965–969
© 2013 British Association of Dermatologists
Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al. 967
Indirect immunofluorescence
Discussion
Indirect immunofluorescence was performed using both healthy human skin and 1 mol L 1 NaCl-split healthy human skin.3 Healthy human skin showed negative results. In contrast, IgA anti-BMZ antibodies reactive with the dermal side of the split were detected in the serum sample obtained 2 days after VCM administration (Fig. 3a), and the sample tested negative after the disappearance of the skin lesions (Fig. 3b). Tests for IgG antibodies were negative.
Among the five VILABD cases examined by immunoblotting, one case had reactivity to unidentified proteins of sizes 83, 130 and 210 kDa; one had reactivity to the 230-kDa protein; one had reactivity to recombinant protein of the BP180 NC16a domain; and the remaining two had reactivity to 180and 285-kDa (LAD285) proteins.10–13 In the present case, we detected for the first time IgA antibodies to the 145- and 165kDa a3 subunits of laminin-332 by immunoblotting analysis. Thus far, no report has been published on the detection of IgA antilaminin-332 antibodies, even in nondrug-induced LABD cases. A previous review of 47 VILABD cases revealed that the male-to-female ratio was 16 : 1 and the age of onset ranged from 32 to 92 years (mean 68 years). It was also reported that the skin lesions appeared 114–16 to 21 days (mean 98 days) after VCM administration, and that the symptoms were alleviated within 60 days (mean 205 days) after VCM discontinuation.1,10–46 In the present case, circulating IgA antilaminin-332 antibodies were detected 2 days after VCM administration. There is no consensus on the blood levels of VCM required to induce LABD.16,22,37,38 Because the blood level of VCM in the present case was within the normal range, a high blood level of VCM was not considered to cause VILABD. Although the previous reports suggested that malignancies or sepsis may facilitate the development of drug-induced LABD,14,37 malignancies were present in only eight of the 47 reported cases of
Immunoblot analyses Immunoblot analyses were performed using normal human epidermal and dermal extracts, concentrated HaCaT cell culture supernatant, recombinant proteins of BP180 NC16a and C-terminal domains, and purified human laminin-332.4–9 All studies were performed for both IgG and IgA antibodies using serum dilution at 1 : 20 and 1 : 10, respectively. IgA antibodies in patient serum samples obtained at the active stage, but not at the remission stage, reacted clearly with the 165- and 145-kDa a3 subunits of laminin-332, while faint reactivity with the same bands was seen for IgG antibodies in the samples obtained at all stages (Fig. 3c). Moreover, IgG, but not IgA, antibodies at all stages also showed faint reactivity with the BP180 C-terminal domain recombinant protein (Fig. 3d). Other immunoblot analyses did not yield any significant results.
(a)
(c)
(d)
(b)
Fig 3. (a, b) The results of indirect immunofluorescence of 1 mol L 1 NaCl-split healthy human skin for serum samples obtained 2 days after vancomycin administration (a), and for serum samples obtained after the disappearance of the skin lesions (b). (c, d) Immunoblot analyses of purified human laminin-332 (c) and BP180 C-terminal domain recombinant protein (d). Sample 1: IgG-1 and IgA-1 measurements were for serum samples obtained 2 days after vancomycin administration. Sample 2: IgG-2 and IgA-2 measurements were for serum samples obtained 12 days after hospitalization at our hospital, before administering prednisolone. Sample 3: IgG-3 and IgA-3 measurements were for serum samples obtained 80 days after hospitalization, when the skin lesions had disappeared. MMP, matrix metalloproteinase; RP, recombinant protein. © 2013 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp965–969
968 Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al.
VILABD (17%). Meticillin-resistant S. aureus sepsis was also observed in the present case, although it is unclear whether the sepsis played a role in the development of LABD. No reports of VILABD cases have indicated the results of patch testing, and the drug-induced lymphocyte stimulation test was performed in only one case and yielded a negative result.41 In most VILABD cases, the diagnoses of VILABD were confirmed by the rapid disappearance of the skin lesions after the discontinuation of VCM. In fact, IgA deposits seen by direct immunofluorescence were not detected when tested soon after the discontinuation of VCM or after the disappearance of skin lesions.1,33,40 In the present case, both the immunofluorescence titre and reactivity with the a3 subunit of laminin-332 became negative after the skin lesion disappeared. In addition, no recurrence was observed thereafter. Most intriguingly, the skin lesions in this case disappeared with prednisolone treatment, despite continuing VCM administration. This phenomenon makes the pathogenic mechanism of VILABD more mysterious, and we have no clear explanation for its occurrence. Additionally, the significance of faint IgG reactivity with both the a3 subunit of laminin-332 and the recombinant protein of BP180 C-terminal domain remains unclear. This reactivity may explain the weak IgG deposit on the BMZ observed by direct immunofluorescence. Although immunofluorescence reactivity with the epidermal side of 1 mol L 1 NaCl-split skin was negative for IgG, IgG antibodies in the patient sera reacted with recombinant protein of the BP180 C-terminal domain by immunoblotting. This is probably because the sensitivity of immunoblotting was higher than that of immunofluorescence. The findings in this case study indicate that VCM administration triggers quick and transient production of IgA autoantibodies in VILABD. The time course of events suggests the possibility that VCM stimulated IgA production in B cells already primed to laminin-332. If this is the case, VCM was not a cause but worked as an enhancer to produce the pathogenic antibody in this case. Therefore, we diagnosed this case as VCM-associated LABD rather than VCM-induced LABD. Further study will be needed to clarify this hypothesis. Finally, detection of IgA antibodies by both indirect immunofluorescence of 1 mol L 1 NaCl-split skin and immunoblot analyses using various antigen sources was useful to establish the definitive diagnosis and choose the treatment strategy.
References 1 Baden LA, Apovian C, Imber MJ, Dover JS. Vancomycin-induced linear IgA bullous dermatosis. Arch Dermatol 1988; 124:1186–8. 2 Fortuna G, Salas-Alanis JC, Guidetti E, Marinkovich MP. 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; 66:988–94. 3 Gammon WR, Briggaman RA, Inman AO 3rd et al. Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescence on 1.0 M sodium chloride-separated skin. J Invest Dermatol 1984; 82:139–44.
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4 Hisamatsu Y, Nishiyama T, Amano S et al. Usefulness of immunoblotting using purified laminin 5 in the diagnosis of anti-laminin 5 cicatricial pemphigoid. J Dermatol Sci 2003; 33:113–19. 5 Ishii N, Ohyama B, Yamaguchi Z, Hashimoto T. IgA autoantibodies against the NC16a domain of BP180 but not 120-kDa LAD-1 detected in a patient with linear IgA disease. Br J Dermatol 2008; 158:1151–3. 6 Sugi T, Hashimoto T, Hibi T, Nishikawa T. Production of human monoclonal anti-basement membrane zone (BMZ) antibodies from a patient with bullous pemphigoid (BP) by Epstein– Barr virus transformation. Analyses of the heterogeneity of antiBMZ antibodies in BP sera using them. J Clin Invest 1989; 84:1050–5. 7 Ishii N, Yoshida M, Hisamatsu Y et al. Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domainspecific recombinant proteins and postembedding immunoelectron microscopy. Br J Dermatol 2004; 150:843–51. 8 Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res 1996; 288:507–9. 9 Nie Z, Hashimoto T. IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180. J Invest Dermatol 1999; 112:254–5. 10 Armstrong AW, Fazeli A, Yeh SW et al. Vancomycin-induced linear IgA disease manifesting as bullous erythema multiforme. J Cutan Pathol 2004; 31:393–7. 11 Hayashi M, Horiguchi Y. A case of linear IgA bullous dermatosis induced by vancomycin chloride. Skin Res 2009; 8:325–30. 12 Tashima S, Konishi K, Koga H, Hashimoto T. A case of vancomycin-induced linear IgA bullous dermatosis with circulating IgA antibodies to the NC16a domain of BP180. Int J Dermatol 2014; 53: e207–9. 13 Palmer RA, Ogg G, Allen J et al. Vancomycin-induced linear IgA disease with autoantibodies to BP180 and LAD285. Br J Dermatol 2001; 145:816–20. 14 Whitworth JM, Thomas I, Peltz SA et al. Vancomycin-induced linear IgA bullous dermatosis (LABD). J Am Acad Dermatol 1996; 34:890–1. 15 Richards SS, Hall S, Yokel B, Whitmore SE. A bullous eruption in an elderly woman. Vancomycin-associated linear IgA dermatosis (LAD). Arch Dermatol 1995; 131:1447–8, 1450–1. 16 Neughebauer BI, Negron G, Pelton S et al. Bullous skin disease: an unusual allergic reaction to vancomycin. Am J Med Sci 2002; 323:273–8. 17 Kuechle MK, Stegemeir E, Maynard B et al. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol 1994; 30:187–92. 18 Carpenter S, Berg D, Sidhu-Malik N et al. Vancomycin-associated linear IgA dermatosis. A report of three cases. J Am Acad Dermatol 1992; 26:45–8. 19 Geissmann C, Beylot-Barry M, Doutre MS, Beylot C. Drug-induced linear IgA bullous dermatosis. J Am Acad Dermatol 1995; 32:296. 20 Bitman LM, Grossman ME, Ross H. Bullous drug eruption treated with amputation. A challenging case of vancomycin-induced linear IgA disease. Arch Dermatol 1996; 132:1289–90. 21 Nousari HC, Costarangos C, Anhalt GJ. Vancomycin-associated linear IgA bullous dermatosis. Ann Intern Med 1998; 129:507–8. 22 Nousari HC, Kimyai-Asadi A, Caeiro JP, Anhalt GJ. Clinical, demographic, and immunohistologic features of vancomycin-induced linear IgA bullous disease of the skin. Report of 2 cases and review of the literature. Medicine (Baltimore) 1999; 78:1–8.
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Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al. 969 23 Mofid MZ, Costarangos C, Bernstein B et al. Drug-induced linear immunoglobulin A bullous disease that clinically mimics toxic epidermal necrolysis. J Burn Care Rehabil 2000; 21:246–7. 24 Wiadrowski TP, Reid CM. Drug-induced linear IgA bullous disease following antibiotics. Australas J Dermatol 2001; 42:196–9. 25 Hughes AP, Callen JP. Drug-induced linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Dermatology 2001; 202:138–9. 26 Ahkami R, Thomas I. Linear IgA bullous dermatosis associated with vancomycin and disseminated varicella-zoster infection. Cutis 2001; 67:423–6. 27 Dellavalle RP, Burch JM, Tayal S et al. Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. J Am Acad Dermatol 2003; 48 (Suppl.):S56–7. 28 Waldman MA, Black DR, Callen JP. Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol 2004; 29:633–6. 29 Solky BA, Pincus L, Horan RF. Vancomycin-induced linear IgA bullous dermatosis: morphology is a key to diagnosis. Cutis 2004; 73:65–7. 30 Navi D, Michael DJ, Fazel N. Drug-induced linear IgA bullous dermatosis. Dermatol Online J 2006; 12:12. 31 Coelho S, Tellechea O, Reis JP et al. Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Int J Dermatol 2006; 45:995–6. 32 Eisendle K, Bonatti H, Sepp N, H€opfl R. Vancomycin-induced linear IgA bullous dermatosis in an immunosuppressed transplant recipient. J Eur Acad Dermatol Venereol 2007; 21:996–7. 33 Billet SE, Kortuem KR, Gibson LE, El-Azhary R. A morbilliform variant of vancomycin-induced linear IgA bullous dermatosis. Arch Dermatol 2008; 144:774–8. 34 McDonald HC, York NR, Pandya AG. Drug-induced linear IgA bullous dermatosis demonstrating the isomorphic phenomenon. J Am Acad Dermatol 2010; 62:897–8.
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35 Jheng-Wei L, Yi-Chin S, Wen-Hung C. Vancomycin-induced linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Indian J Dermatol Venereol Leprol 2011; 77:537. 36 Selvaraj PK, Khasawneh FA. Linear IgA bullous dermatosis: a rare side effect of vancomycin. Ann Saudi Med 2013; 33:397–9. 37 Klein PA, Callen JP. Drug-induced linear IgA bullous dermatosis after vancomycin discontinuance in a patient with renal insufficiency. J Am Acad Dermatol 2000; 42:316–23. 38 Walsh SN, Kerchner K, Sangueza OP. Localized palmar vancomycin-induced linear IgA bullous dermatosis occurring at supratherapeutic levels. Arch Dermatol 2009; 145:603–4. 39 Joshi S, Scott G, Looney RJ. A successful challenge in a patient with vancomycin-induced linear IgA dermatosis. Ann Allergy Asthma Immunol 2004; 93:101–3. 40 Piketty C, Meeus F, Nochy D et al. Linear IgA dermatosis related to vancomycin. Br J Dermatol 1994; 130:130–1. 41 Onodera H, Mihm MC Jr, Yoshida A, Akasaka T. Drug-induced linear IgA bullous dermatosis. J Dermatol 2005; 32:759–64. 42 Yamanaka S, Sugihara A, Horio T. A case of vancomycin hydrochloride-induced linear IgA bullous dermatosis. Jpn J Dermatol 2006; 116:2285–90. 43 Ogawa T, Ikezawa Y, Hirokado M. A case of toxic epidermal necrolysis recovered markedly by plasma exchenge. Skin Res 2009; 8:318–24. 44 Taguchi K, Bito T, Nishigori C. A case of vancomycin hydrochloride-induced linear IgA bullous dermatosis. Skin Res 2009; 7:317– 21. 45 Arakawa S, Anan T, Anzai S et al. Three cases of linear IgA bullous dermatosis. Nishinihon J Dermatol 2008; 70:377–80. 46 Okita M, Fujimoto T, Wakabayashi M et al. A case of drug-induced linear IgA bullous dermatosis. Rinsho Derma 2012; 54:1695–8.
British Journal of Dermatology (2014) 170, pp965–969
British Journal of Dermatology
CASE REPORT
A case of vancomycin-associated linear IgA bullous dermatosis and IgA antibodies to the a3 subunit of laminin-332 Y. Zenke,1 T. Nakano,1 H. Eto,1 H. Koga2 and T. Hashimoto2 1 2
Department of Dermatology, St Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan Department of Dermatology, Kurume University School of Medicine, and Institute of Cutaneous Cell Biology, Kurume, Fukuoka, Japan
Summary Correspondence Yukari Zenke. E-mail: [email protected]
Accepted for publication 2 November 2013
Funding sources None.
Conflicts of interest None declared. DOI 10.1111/bjd.12720
Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disease, which is defined by the histopathological finding of subepidermal vesicles with neutrophilic infiltration and linear IgA deposits in the basement membrane zone, revealed by immunofluorescence study. We present a case of LABD in which vancomycin (VCM) administration triggered LABD, and immunoblot analysis showed IgA antibodies reactive to the 145- and 165-kDa a3 subunits of laminin332. This is the first report of VCM-associated LABD in which the target antigen was laminin-332. In the present case, we were compelled to continue administration of VCM along with systemic steroids, which eventually led to the attenuation of the symptoms, normalization of the serum IgA level, and negative results on both indirect immunofluorescence of 1 mol L 1 NaCl-split skin and immunoblot analysis.
What’s already known about this topic?
•
Vancomycin-induced linear IgA bullous dermatosis (LABD) comprises 46% of drug-induced LABD cases and involves reactivity to 83-, 130-, 180-, 230- and 285-kDa proteins.
What does this study add?
• •
We present the first case of vancomycin-associated LABD with IgA antibodies to the a3 subunit of laminin-332. The results of serum IgA level measurement, indirect immunofluorescence and immunoblot analysis were useful to determine the treatment.
Linear IgA bullous dermatosis (LABD) is clinically characterized by the appearance of multiple small itchy bullae within annular erythema on the entire body; the immunological characteristic is linear deposits of IgA on the basement membrane zone (BMZ). Drugs known to induce LABD include captopril, trimethoprim with sulfamethoxazole, phenytoin and diclofenac. Vancomycin (VCM)-induced LABD (VILABD) was first reported in 1988 by Baden et al.;1 thereafter, VCM has been reported as the most common cause of drug-induced LABD, accounting for 462% of cases.2 Immunoblot analysis has been performed in only five cases of VILABD reported previously. This report is the first to present a case of VCM-associated © 2013 British Association of Dermatologists
LABD with evidence of IgA antibodies to the 145- and 165kDa a3 subunits of laminin-332.
Case report A 62-year-old Japanese man, who was treated for brain-stem haemorrhage and diabetes at another hospital, developed infective endocarditis and was transferred to the internal medicine department at our hospital. VCM treatment had started 2 days before admission to our hospital. According to his previous medical record, there was no history of VCM therapy. Rifampicin, sulfamethoxazole with trimethoprim, tazobactam British Journal of Dermatology (2014) 170, pp965–969
965
966 Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al.
with piperacillin and other drugs were administered after hospitalization at our hospital. Ten days after the initiation of intravenous VCM 500 mg per day, oedematous erythema appeared on the trunk. Twelve days later, small-to-mediumsized tense bullae and erosions appeared on the axillae, chest, thighs and buttocks (Fig. 1a). No mucosal lesions were noted and the Nikolsky sign was negative. The blood trough level of VCM at the onset of the erythema was 168 lg mL 1 (normal range 10–20 lg mL 1), and the serum IgA level was 633 mg dL 1 (normal range 110– 410 mg dL 1). The results of IgG enzyme-linked immunosorbent assays for circulating antibodies to BP180 and BP230 were negative. Meticillin-resistant Staphylococcus aureus was detected by blood culture. Initially, we suspected drug eruption, and therefore we discontinued all the drugs other than VCM. VCM was continued because the infectious endocarditis and sepsis had not yet been adequately controlled. Subsequently, intravenous methylprednisolone (60 mg per day) was administered for the first 3 days.
(a)
(b)
However, tense bullae continued to develop on the scrotum and extremities (Fig. 1b); therefore, we restarted methylprednisolone therapy 8 days after the completion of the previous course. VILABD was suspected, and a skin biopsy sample was obtained from a bulla on the abdomen 12 days after hospitalization. Histopathological examination of the sample revealed formation of subepidermal bullae, as well as infiltration of lymphocytes and neutrophils in the upper dermis (Fig. 1c). Direct immunofluorescence of the skin biopsy revealed linear IgA deposits on the BMZ (Fig. 1d). IgG was minimally positive to the BMZ. Both patch test and a drug-induced lymphocyte stimulation test for VCM were performed approximately 1 month after disappearance of the skin lesions and showed negative results. Although VCM was continued, systemic prednisolone suppressed the skin lesions and they reduced gradually. The skin lesions disappeared 45 days after admission, while VCM was still being continued. There was no recurrence and the serum IgA level normalized to 397 mg dL 1 (Fig. 2).
(c)
(d) Fig 1. Clinical manifestations 12 days after the initiation of vancomycin (a) and after the initiation of prednisolone (b). (c) Histopathological findings of skin biopsy (2009, haematoxylin and eosin staining). (d) Direct immunofluorescence for IgA.
Fig 2. Time graph with data on medication, disease activity (blistering) and blood sampling. mPSL, methylprednisolone; VCM, vancomycin. British Journal of Dermatology (2014) 170, pp965–969
© 2013 British Association of Dermatologists
Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al. 967
Indirect immunofluorescence
Discussion
Indirect immunofluorescence was performed using both healthy human skin and 1 mol L 1 NaCl-split healthy human skin.3 Healthy human skin showed negative results. In contrast, IgA anti-BMZ antibodies reactive with the dermal side of the split were detected in the serum sample obtained 2 days after VCM administration (Fig. 3a), and the sample tested negative after the disappearance of the skin lesions (Fig. 3b). Tests for IgG antibodies were negative.
Among the five VILABD cases examined by immunoblotting, one case had reactivity to unidentified proteins of sizes 83, 130 and 210 kDa; one had reactivity to the 230-kDa protein; one had reactivity to recombinant protein of the BP180 NC16a domain; and the remaining two had reactivity to 180and 285-kDa (LAD285) proteins.10–13 In the present case, we detected for the first time IgA antibodies to the 145- and 165kDa a3 subunits of laminin-332 by immunoblotting analysis. Thus far, no report has been published on the detection of IgA antilaminin-332 antibodies, even in nondrug-induced LABD cases. A previous review of 47 VILABD cases revealed that the male-to-female ratio was 16 : 1 and the age of onset ranged from 32 to 92 years (mean 68 years). It was also reported that the skin lesions appeared 114–16 to 21 days (mean 98 days) after VCM administration, and that the symptoms were alleviated within 60 days (mean 205 days) after VCM discontinuation.1,10–46 In the present case, circulating IgA antilaminin-332 antibodies were detected 2 days after VCM administration. There is no consensus on the blood levels of VCM required to induce LABD.16,22,37,38 Because the blood level of VCM in the present case was within the normal range, a high blood level of VCM was not considered to cause VILABD. Although the previous reports suggested that malignancies or sepsis may facilitate the development of drug-induced LABD,14,37 malignancies were present in only eight of the 47 reported cases of
Immunoblot analyses Immunoblot analyses were performed using normal human epidermal and dermal extracts, concentrated HaCaT cell culture supernatant, recombinant proteins of BP180 NC16a and C-terminal domains, and purified human laminin-332.4–9 All studies were performed for both IgG and IgA antibodies using serum dilution at 1 : 20 and 1 : 10, respectively. IgA antibodies in patient serum samples obtained at the active stage, but not at the remission stage, reacted clearly with the 165- and 145-kDa a3 subunits of laminin-332, while faint reactivity with the same bands was seen for IgG antibodies in the samples obtained at all stages (Fig. 3c). Moreover, IgG, but not IgA, antibodies at all stages also showed faint reactivity with the BP180 C-terminal domain recombinant protein (Fig. 3d). Other immunoblot analyses did not yield any significant results.
(a)
(c)
(d)
(b)
Fig 3. (a, b) The results of indirect immunofluorescence of 1 mol L 1 NaCl-split healthy human skin for serum samples obtained 2 days after vancomycin administration (a), and for serum samples obtained after the disappearance of the skin lesions (b). (c, d) Immunoblot analyses of purified human laminin-332 (c) and BP180 C-terminal domain recombinant protein (d). Sample 1: IgG-1 and IgA-1 measurements were for serum samples obtained 2 days after vancomycin administration. Sample 2: IgG-2 and IgA-2 measurements were for serum samples obtained 12 days after hospitalization at our hospital, before administering prednisolone. Sample 3: IgG-3 and IgA-3 measurements were for serum samples obtained 80 days after hospitalization, when the skin lesions had disappeared. MMP, matrix metalloproteinase; RP, recombinant protein. © 2013 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp965–969
968 Vancomycin-induced LABD reactive with antilaminin-332, Y. Zenke et al.
VILABD (17%). Meticillin-resistant S. aureus sepsis was also observed in the present case, although it is unclear whether the sepsis played a role in the development of LABD. No reports of VILABD cases have indicated the results of patch testing, and the drug-induced lymphocyte stimulation test was performed in only one case and yielded a negative result.41 In most VILABD cases, the diagnoses of VILABD were confirmed by the rapid disappearance of the skin lesions after the discontinuation of VCM. In fact, IgA deposits seen by direct immunofluorescence were not detected when tested soon after the discontinuation of VCM or after the disappearance of skin lesions.1,33,40 In the present case, both the immunofluorescence titre and reactivity with the a3 subunit of laminin-332 became negative after the skin lesion disappeared. In addition, no recurrence was observed thereafter. Most intriguingly, the skin lesions in this case disappeared with prednisolone treatment, despite continuing VCM administration. This phenomenon makes the pathogenic mechanism of VILABD more mysterious, and we have no clear explanation for its occurrence. Additionally, the significance of faint IgG reactivity with both the a3 subunit of laminin-332 and the recombinant protein of BP180 C-terminal domain remains unclear. This reactivity may explain the weak IgG deposit on the BMZ observed by direct immunofluorescence. Although immunofluorescence reactivity with the epidermal side of 1 mol L 1 NaCl-split skin was negative for IgG, IgG antibodies in the patient sera reacted with recombinant protein of the BP180 C-terminal domain by immunoblotting. This is probably because the sensitivity of immunoblotting was higher than that of immunofluorescence. The findings in this case study indicate that VCM administration triggers quick and transient production of IgA autoantibodies in VILABD. The time course of events suggests the possibility that VCM stimulated IgA production in B cells already primed to laminin-332. If this is the case, VCM was not a cause but worked as an enhancer to produce the pathogenic antibody in this case. Therefore, we diagnosed this case as VCM-associated LABD rather than VCM-induced LABD. Further study will be needed to clarify this hypothesis. Finally, detection of IgA antibodies by both indirect immunofluorescence of 1 mol L 1 NaCl-split skin and immunoblot analyses using various antigen sources was useful to establish the definitive diagnosis and choose the treatment strategy.
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