Pediatric Dermatology Vol. 32 No. 5 723–726, 2015
Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin: Case Report and Review of the Literature Burak Tekin, M.D., and Aysße Deniz Y€ ucelten, M.D. Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey
Abstract: We report a 5-month-old girl diagnosed with bullous pemphigoid who initially did not respond to systemic corticosteroids and dapsone but rapidly improved after the addition of intravenous immunoglobulin (IVIG) infusions. A literature search revealed anecdotal cases of infantile bullous pemphigoid treated with IVIG, although variable treatment regimens were used, and some resistant cases required additional medications such as rituximab for clinical remission.
A 5-month-old girl was referred for a pruritic erythematous blistering rash beginning on the palms and soles 1 month before and generalizing within the next 2 weeks despite treatment with potent topical corticosteroids. She had received the pneumococcal conjugate vaccine 1 week before the appearance of the skin lesions. Her family history was unremarkable. Examination revealed widespread urticarial papules and plaques with annular and polycyclic shapes, multiple erosions, and vesiculobullous lesions on the face, trunk, and extremities. Mucous membranes were spared and Nikolsky sign was absent. The total peripheral white blood cell count was 25,200/lL, with prominent eosinophilia of 40% (absolute eosinophil count 10,080/lL). A skin biopsy specimen from an intact blister showed subepidermal blistering with a mixed inflammatory cell infiltrate containing many eosinophils. Direct immunofluorescence of the perilesional skin showed linear deposits of immunoglobulin
G and ILC3 along the epidermal basal membrane zone, and an enzyme-linked immunosorbent assay for the NC16A domain of BP180 was positive (106 U/ mL), supporting the diagnosis of bullous pemphigoid. Systemic treatment was begun with approximately 2 mg/kg/day of oral methylprednisolone and 1 mg/ kg/day of dapsone; the dose of dapsone was increased to 2 mg/kg/day 1 week later (Fig. 1). After slight improvement, erythema generalized, with new bullae and erosions continuing to appear, covering almost the entire body (Fig. 2A). The patient was admitted, and two 5-day courses of intravenous immunoglogulin (IVIG; 400 mg/kg/day, 2.5 wks apart) were administered, leading to cessation of new blister formation and a rapid resolution of erythema and eroded areas. The skin was almost clear approximately 1 week after the second IVIG course (Fig. 2B), with a reduction in white blood cell and eosinophil counts.
Address correspondence to Aysße Deniz Y€ ucelten, Mimar Sinan € Kaynarca Fevzi C Caddesi No: 41 Ust ß akmak Mahallesi Pendik, Istanbul, Turkey, or e-mail: [email protected]. DOI: 10.1111/pde.12635
© 2015 Wiley Periodicals, Inc.
723
724 Pediatric Dermatology Vol. 32 No. 5 September/October 2015
Figure 1. Chronological overview of systemic dermatologic treatments.
A
B
Figure 2. (A) Annular and polycyclic plaques, erosions, and vesiculobullous lesions on the trunk and proximal extremities covering almost the entire body before the first intravenous immunoglobulin (IVIG) course. (B) Postinflammatory hypopigmentation 1 week after the second IVIG course.
After discharge, treatment was continued with the same dose of dapsone for 1 year while methylprednisolone was slowly tapered and stopped within a 7-month period. Two more courses of IVIG were given, spaced at increasingly longer intervals (Fig. 1). IVIG infusions were generally well tolerated. Vaccinations were not given during treatment and were resumed 1 month after discontinuation of methylprednisolone. No relapse has been seen during a 23month follow-up period, and the patient had been off therapy for her skin disease for the 7 months at writing of this report. DISCUSSION Bullous pemphigoid is considered an acquired autoimmune subepidermal blistering disorder of elderly adults that is rarely seen in infants and older children. Several clinical features distinguish infantile bullous
pemphigoid (IBP) from its counterpart in older children; it more commonly presents on the palms, soles, and face, and genital involvement is seen less frequently. Generalized involvement as seen in our patient is more likely in infants (1). A possible link between IBP and vaccinations has been described, although this may represent a temporal and not necessarily a causal relationship since many routine immunizations are performed within the first year of life (1,2). Although IBP usually responds well to first-line therapy with systemic corticosteroids, resistant cases have been reported. A literature search revealed anecdotal cases of IBP treated using IVIG (Table 1) (1–8). Variable dosages (200 mg/kg/day to 1 g/kg/ day), infusion courses (2- to 5-day courses), and intervals (2–5 wks) were used, probably reflecting the heterogeneity of institutional or individual preferences regarding IVIG treatment in general.
Tekin and Y€ ucelten: Treatment of Infantile Bullous Pemphigoid Using IVIG 725
TABLE 1. Reported Cases of Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin (IVIG)
Reference
Age at diagnosis, months
Sex
Systemic medications used before or with first IVIG infusion
Courses of IVIG, n
Interval between courses, length of each course, and dosage
Addition of other systemic treatment needed for remission after IVIG
Multiple*
2 g/kg every 2 wks
No
Multiple*
2-day courses (700 mg/kg/day to 1 g/kg/day) every 2–3 wks 5-day course (5 g/day)
No
Waisbourd-Zinman et al (1) Ister et al (2)
4
Female
3
Male
Corticosteroids, dapsone, mycophenolate mofetil Corticosteroids
Tr€ ueb et al (3)
8
Male
Dapsone, corticosteroids
1
Xiao et al (4)
3.5
Male
None
1
Female
Corticosteroids
7
Corticosteroids, dapsone, erythromycin Corticosteroids, dapsone
2
Corticosteroids, azathioprine Corticosteroids, dapsone
Multiple*
Nanda et al (5)
13
Sugawara et al (6)
3
Male
Schulze et al (7)
5
Male
Fuertes et al (8)
7
Male
Current case
5
Female
~7
4
4-day course (400 mg/kg/day) Monthly 5-day courses (400 mg/kg/day) 5-day courses (300 mg/kg/day) First three courses every 5 wks, subsequent courses monthly (2 g/kg) 5-day courses every 3 wks (200 mg/kg/day) 5-day courses (400 mg/kg/day)
Yes (cyclosporine, pulse corticosteroids) No Yes (dapsone) No Yes (mycophenolate mofetil, cyclosporine, rituximab) Yes (rituximab, mycophenolate mofetil) No
*Exact number of courses not stated in the article.
The IVIG dosing scheme of the current case (400 mg/kg/day for 5 consecutive days per infusion cycle) corresponds to the high-dose regimen employed for the treatment of bullous pemphigoid (9) and other autoimmune bullous diseases (10) in adults. Similar regimens were also preferred in other cases of IBP (3– 6,8). In the majority of the reviewed cases, clinical remission was obtained after the introduction of IVIG, although in two cases (7,8) rituximab had to be added. The case report by Xiao et al (4) is noteworthy in that excellent clinical response was obtained briefly after a single IVIG course, without using systemic corticosteroids. Similarly, the first IVIG course led to cessation of new lesion development in the case report by Sugawara et al (6), although recurrence was seen 3 weeks later that was successfully managed with a second course of IVIG. In most of the other cases reviewed here (1,2,5,7,8), more than two treatment courses were administered. In a review article about the treatment of adult bullous pemphigoid using IVIG, the authors shared their observation that more than one infusion cycle yielded a better prognosis, with longer remissions than a single cycle (9), although a similar conclusion cannot be reliably drawn for IBP at the moment since the number of reported cases is small. Nevertheless, we assumed that repeated courses of IVIG might allow a more rapid taper of corticosteroids, which
have many potential adverse effects, including growth retardation in childhood. Based on this, we administered two more IVIG courses after clearance of skin lesions while tapering corticosteroids. We were also concerned that our patient’s IBP might relapse, as did the patient of Sugawara et al (6), if we did not repeat the IVIG infusions. IVIG can be considered a relatively safe therapeutic option for infants. A Cochrane review of the prophylactic use of IVIG for the prevention of infections encompassing approximately 5,000 preterm and low-birthweight infants revealed no short-term IVIG-related serious side effects and a lower rate of serious infections (11). Likewise, there were no serious adverse effects directly attributable to IVIG among the cases of IBP reviewed here. Moreover, IVIG was preferred over immunosuppressive therapies in a case with tuberculous meningoencephalitis (5) and another case with cytomegalovirus infection (6), indicating that IVIG may be safely used for the treatment of IBP complicated by infection. Based on this and other anecdotal reports, IVIG seems to be a highly effective and safe treatment for IBP refractory to systemic corticosteroids and dapsone. Large-scale multicenter clinical trials are needed to determine the efficacy and optimal regimen of IVIG in the treatment of steroid-refractory IBP, which may be virtually impossible in such a rare disorder.
726 Pediatric Dermatology Vol. 32 No. 5 September/October 2015
REFERENCES 1. Waisbourd-Zinman O, Ben-Amitai D, Cohen AD et al. Bullous pemphigoid in infancy: clinical and epidemiologic characteristics. J Am Acad Dermatol 2008;58:41–48. 2. Ister M, Pouessel G, Ythier H et al. Postvaccinal, corticosteroid-resistant bullous pemphigoid in infancy: treatment with intravenous immunoglobulin. Pediatr Dermatol 2014;31:e94–e95. 3. Tr€ ueb RM, Didierjean L, Fellas A et al. Childhood bullous pemphigoid: report of a case with characterization of the targeted antigens. J Am Acad Dermatol 1999;40:338–344. 4. Xiao T, Li B, Wang YK et al. Childhood bullous pemphigoid treated by i.v. immunoglobulin. J Dermatol 2007;34:650–653. 5. Nanda A, Nanda M, Dvorak R et al. Bullous pemphigoid (BP) in an infant complicated by tuberculous meningoencephalitis. Int J Dermatol 2007;46:964–966. 6. Sugawara N, Nagai Y, Matsushima Y et al. Infantile bullous pemphigoid treated with intravenous
7. 8. 9.
10.
11.
immunoglobulin therapy. J Am Acad Dermatol 2007;57:1084–1089. Schulze J, Bader P, Henke U et al. Severe bullous pemphigoid in an infant-successful treatment with rituximab. Pediatr Dermatol 2008;25:462–465. Fuertes I, Luelmo J, Leal L et al. Refractory childhood pemphigoid successfully treated with rituximab. Pediatr Dermatol 2013;30:e96–e97. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol 2001;44:83–88. Segura S, Iranzo P, Martınez-de Pablo I et al. Highdose intravenous immunoglobulins for the treatment of autoimmune mucocutaneous blistering diseases: evaluation of its use in 19 cases. J Am Acad Dermatol 2007;56:960–967. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2013;7: CD000361.
Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin: Case Report and Review of the Literature Burak Tekin, M.D., and Aysße Deniz Y€ ucelten, M.D. Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey
Abstract: We report a 5-month-old girl diagnosed with bullous pemphigoid who initially did not respond to systemic corticosteroids and dapsone but rapidly improved after the addition of intravenous immunoglobulin (IVIG) infusions. A literature search revealed anecdotal cases of infantile bullous pemphigoid treated with IVIG, although variable treatment regimens were used, and some resistant cases required additional medications such as rituximab for clinical remission.
A 5-month-old girl was referred for a pruritic erythematous blistering rash beginning on the palms and soles 1 month before and generalizing within the next 2 weeks despite treatment with potent topical corticosteroids. She had received the pneumococcal conjugate vaccine 1 week before the appearance of the skin lesions. Her family history was unremarkable. Examination revealed widespread urticarial papules and plaques with annular and polycyclic shapes, multiple erosions, and vesiculobullous lesions on the face, trunk, and extremities. Mucous membranes were spared and Nikolsky sign was absent. The total peripheral white blood cell count was 25,200/lL, with prominent eosinophilia of 40% (absolute eosinophil count 10,080/lL). A skin biopsy specimen from an intact blister showed subepidermal blistering with a mixed inflammatory cell infiltrate containing many eosinophils. Direct immunofluorescence of the perilesional skin showed linear deposits of immunoglobulin
G and ILC3 along the epidermal basal membrane zone, and an enzyme-linked immunosorbent assay for the NC16A domain of BP180 was positive (106 U/ mL), supporting the diagnosis of bullous pemphigoid. Systemic treatment was begun with approximately 2 mg/kg/day of oral methylprednisolone and 1 mg/ kg/day of dapsone; the dose of dapsone was increased to 2 mg/kg/day 1 week later (Fig. 1). After slight improvement, erythema generalized, with new bullae and erosions continuing to appear, covering almost the entire body (Fig. 2A). The patient was admitted, and two 5-day courses of intravenous immunoglogulin (IVIG; 400 mg/kg/day, 2.5 wks apart) were administered, leading to cessation of new blister formation and a rapid resolution of erythema and eroded areas. The skin was almost clear approximately 1 week after the second IVIG course (Fig. 2B), with a reduction in white blood cell and eosinophil counts.
Address correspondence to Aysße Deniz Y€ ucelten, Mimar Sinan € Kaynarca Fevzi C Caddesi No: 41 Ust ß akmak Mahallesi Pendik, Istanbul, Turkey, or e-mail: [email protected]. DOI: 10.1111/pde.12635
© 2015 Wiley Periodicals, Inc.
723
724 Pediatric Dermatology Vol. 32 No. 5 September/October 2015
Figure 1. Chronological overview of systemic dermatologic treatments.
A
B
Figure 2. (A) Annular and polycyclic plaques, erosions, and vesiculobullous lesions on the trunk and proximal extremities covering almost the entire body before the first intravenous immunoglobulin (IVIG) course. (B) Postinflammatory hypopigmentation 1 week after the second IVIG course.
After discharge, treatment was continued with the same dose of dapsone for 1 year while methylprednisolone was slowly tapered and stopped within a 7-month period. Two more courses of IVIG were given, spaced at increasingly longer intervals (Fig. 1). IVIG infusions were generally well tolerated. Vaccinations were not given during treatment and were resumed 1 month after discontinuation of methylprednisolone. No relapse has been seen during a 23month follow-up period, and the patient had been off therapy for her skin disease for the 7 months at writing of this report. DISCUSSION Bullous pemphigoid is considered an acquired autoimmune subepidermal blistering disorder of elderly adults that is rarely seen in infants and older children. Several clinical features distinguish infantile bullous
pemphigoid (IBP) from its counterpart in older children; it more commonly presents on the palms, soles, and face, and genital involvement is seen less frequently. Generalized involvement as seen in our patient is more likely in infants (1). A possible link between IBP and vaccinations has been described, although this may represent a temporal and not necessarily a causal relationship since many routine immunizations are performed within the first year of life (1,2). Although IBP usually responds well to first-line therapy with systemic corticosteroids, resistant cases have been reported. A literature search revealed anecdotal cases of IBP treated using IVIG (Table 1) (1–8). Variable dosages (200 mg/kg/day to 1 g/kg/ day), infusion courses (2- to 5-day courses), and intervals (2–5 wks) were used, probably reflecting the heterogeneity of institutional or individual preferences regarding IVIG treatment in general.
Tekin and Y€ ucelten: Treatment of Infantile Bullous Pemphigoid Using IVIG 725
TABLE 1. Reported Cases of Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin (IVIG)
Reference
Age at diagnosis, months
Sex
Systemic medications used before or with first IVIG infusion
Courses of IVIG, n
Interval between courses, length of each course, and dosage
Addition of other systemic treatment needed for remission after IVIG
Multiple*
2 g/kg every 2 wks
No
Multiple*
2-day courses (700 mg/kg/day to 1 g/kg/day) every 2–3 wks 5-day course (5 g/day)
No
Waisbourd-Zinman et al (1) Ister et al (2)
4
Female
3
Male
Corticosteroids, dapsone, mycophenolate mofetil Corticosteroids
Tr€ ueb et al (3)
8
Male
Dapsone, corticosteroids
1
Xiao et al (4)
3.5
Male
None
1
Female
Corticosteroids
7
Corticosteroids, dapsone, erythromycin Corticosteroids, dapsone
2
Corticosteroids, azathioprine Corticosteroids, dapsone
Multiple*
Nanda et al (5)
13
Sugawara et al (6)
3
Male
Schulze et al (7)
5
Male
Fuertes et al (8)
7
Male
Current case
5
Female
~7
4
4-day course (400 mg/kg/day) Monthly 5-day courses (400 mg/kg/day) 5-day courses (300 mg/kg/day) First three courses every 5 wks, subsequent courses monthly (2 g/kg) 5-day courses every 3 wks (200 mg/kg/day) 5-day courses (400 mg/kg/day)
Yes (cyclosporine, pulse corticosteroids) No Yes (dapsone) No Yes (mycophenolate mofetil, cyclosporine, rituximab) Yes (rituximab, mycophenolate mofetil) No
*Exact number of courses not stated in the article.
The IVIG dosing scheme of the current case (400 mg/kg/day for 5 consecutive days per infusion cycle) corresponds to the high-dose regimen employed for the treatment of bullous pemphigoid (9) and other autoimmune bullous diseases (10) in adults. Similar regimens were also preferred in other cases of IBP (3– 6,8). In the majority of the reviewed cases, clinical remission was obtained after the introduction of IVIG, although in two cases (7,8) rituximab had to be added. The case report by Xiao et al (4) is noteworthy in that excellent clinical response was obtained briefly after a single IVIG course, without using systemic corticosteroids. Similarly, the first IVIG course led to cessation of new lesion development in the case report by Sugawara et al (6), although recurrence was seen 3 weeks later that was successfully managed with a second course of IVIG. In most of the other cases reviewed here (1,2,5,7,8), more than two treatment courses were administered. In a review article about the treatment of adult bullous pemphigoid using IVIG, the authors shared their observation that more than one infusion cycle yielded a better prognosis, with longer remissions than a single cycle (9), although a similar conclusion cannot be reliably drawn for IBP at the moment since the number of reported cases is small. Nevertheless, we assumed that repeated courses of IVIG might allow a more rapid taper of corticosteroids, which
have many potential adverse effects, including growth retardation in childhood. Based on this, we administered two more IVIG courses after clearance of skin lesions while tapering corticosteroids. We were also concerned that our patient’s IBP might relapse, as did the patient of Sugawara et al (6), if we did not repeat the IVIG infusions. IVIG can be considered a relatively safe therapeutic option for infants. A Cochrane review of the prophylactic use of IVIG for the prevention of infections encompassing approximately 5,000 preterm and low-birthweight infants revealed no short-term IVIG-related serious side effects and a lower rate of serious infections (11). Likewise, there were no serious adverse effects directly attributable to IVIG among the cases of IBP reviewed here. Moreover, IVIG was preferred over immunosuppressive therapies in a case with tuberculous meningoencephalitis (5) and another case with cytomegalovirus infection (6), indicating that IVIG may be safely used for the treatment of IBP complicated by infection. Based on this and other anecdotal reports, IVIG seems to be a highly effective and safe treatment for IBP refractory to systemic corticosteroids and dapsone. Large-scale multicenter clinical trials are needed to determine the efficacy and optimal regimen of IVIG in the treatment of steroid-refractory IBP, which may be virtually impossible in such a rare disorder.
726 Pediatric Dermatology Vol. 32 No. 5 September/October 2015
REFERENCES 1. Waisbourd-Zinman O, Ben-Amitai D, Cohen AD et al. Bullous pemphigoid in infancy: clinical and epidemiologic characteristics. J Am Acad Dermatol 2008;58:41–48. 2. Ister M, Pouessel G, Ythier H et al. Postvaccinal, corticosteroid-resistant bullous pemphigoid in infancy: treatment with intravenous immunoglobulin. Pediatr Dermatol 2014;31:e94–e95. 3. Tr€ ueb RM, Didierjean L, Fellas A et al. Childhood bullous pemphigoid: report of a case with characterization of the targeted antigens. J Am Acad Dermatol 1999;40:338–344. 4. Xiao T, Li B, Wang YK et al. Childhood bullous pemphigoid treated by i.v. immunoglobulin. J Dermatol 2007;34:650–653. 5. Nanda A, Nanda M, Dvorak R et al. Bullous pemphigoid (BP) in an infant complicated by tuberculous meningoencephalitis. Int J Dermatol 2007;46:964–966. 6. Sugawara N, Nagai Y, Matsushima Y et al. Infantile bullous pemphigoid treated with intravenous
7. 8. 9.
10.
11.
immunoglobulin therapy. J Am Acad Dermatol 2007;57:1084–1089. Schulze J, Bader P, Henke U et al. Severe bullous pemphigoid in an infant-successful treatment with rituximab. Pediatr Dermatol 2008;25:462–465. Fuertes I, Luelmo J, Leal L et al. Refractory childhood pemphigoid successfully treated with rituximab. Pediatr Dermatol 2013;30:e96–e97. Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol 2001;44:83–88. Segura S, Iranzo P, Martınez-de Pablo I et al. Highdose intravenous immunoglobulins for the treatment of autoimmune mucocutaneous blistering diseases: evaluation of its use in 19 cases. J Am Acad Dermatol 2007;56:960–967. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2013;7: CD000361.
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