3. Lichtenstein DA, Klapholz L, Vardy DA, et al. Chronic radiodermatitis following cardiac catheterization. Arch Dermatol 1996; 132: 6637. 4. Georges JL, Pesenti-Rossi D, Livarek B. Controlling the radiation dose received by patients undergoing cardiac imaging. Future Cardiol 2011; 7: 1-5. 5. Delanian S, Porcher R, Rudant J, Lefaix JL. Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J Clin Oncol 2005; 23: 8570-9. doi:10.1684/ejd.2014.2315
Bullous pemphigoid in a renal transplant recipient Bullous pemphigoid (BP) is a subepidermal autoimmune bullous disease mediated by autoantibodies directed toward antigens (BPAg1-230, BPAg2-180) located in hemidesmosomes and the lamina lucida of the dermal-epidermal junction. BP is usually idiopathic but multiple etiological agents (drugs, physical stimulation, cancers and immune abnormalities) have been identified [1]. We report a 59 yearold kidney-transplant recipient who developed an itchy rash with lichenoid features on the trunk and back nine years post-transplantation. She had undergone hemodialysis from 1998 to 2003 for membranous glomerulonephritis (MGN). In July 2003 she received a cadaveric renal transplant and started an immunosuppressive treatment (tacrolimus 4 mg/d and prednisone 10 mg/d). At the first dermatological visit she did not report any significant comorbidities or other drug intake. Serum creatinine and blood urea nitrogen were 1.2 and 19.6 mg/dL, respectively. Topical and systemic steroids and antihistamines brought a partial clinical benefit, with recurrence at treatment discontinuation. In June 2012, the patient developed bullous lesions on the right breast, initially successfully treated with topical methylprednisolone. After three months new bullous and ulcerated lesions with widespread desquamation on the trunk, upper back and limbs developed (figure 1A). A skin biopsy revealed a subepidermal bulla (figure 1B). Direct immunofluorescence demonstrated IgG and granular C3 deposits at the dermal-epidermal junction (figure 1C). Indirect immunofluorescence showed antibodies binding to the epidermal side of salt-split skin. ELISA testing showed circulating antibodies to BP180 (31 UI/mL) but not to BP230. These findings led to the diagnosis of BP. Positive-emission tomography ruled out an underlying malignancy. Intravenous methylprednisolone (1 mg/kg/d) was started together with oral diamino-diphenyl-sulfone (DDS; 100 mg/d) with a rapid clinical benefit and starting re-epithelialization of the ulcerated lesions. Steroids were gradually tapered to 15 mg/d. One month later, new pruritic bullae appeared on the trunk. Prednisolone was increased to 50 mg/d and then progressively tapered to 15 mg/d. Because of high methaemoglobin blood levels and mild dyspnea, DDS was reduced to 50 mg/d and finally discontinued. At the latest follow-up (December 2013), the cutaneous lesions had completely regressed. EJD, vol. 24, n◦ 3, May-June 2014
BP has rarely been reported associated with renal diseases. Its association with MGN could be due to cross-reactivity to common epitopes present in the cutaneous and renal basement membranes. Renal antigens have never been clearly identified [2] but could be similar to BPAg1 and BPAg2. Some have claimed that BP and MGN represent two distinct manifestations of a generalized autoimmune disorder [3]. BP has been associated with many other autoimmune disorders [4]. A common trigger could be responsible for the development of separate antibodies that attack different antigens in distinct organs. The occurrence of BP in association with renal transplantation is rare; only 11 such cases have been reported [5-9]. Various mechanisms could explain this event. Skin lesions may be caused by acute graft rejection with an immunological cross-reaction between the allograft and the skin. Alternatively, the graft could act as a chronic allogenic stimulus able to induce autoantibodies against antigens of the dermal-epidermal junction. In most cases, the bullous eruption occurred after organ rejection and was often preceded by reduction or withdrawal of immunosuppression. The removal of the allograft was often followed by complete remission [7]. Some authors [8] have hypothesized a causative role of the immunosuppressive drugs. The clinicopathological findings of BP derive from complex interactions between T-cell immunity and B-cell-mediated antibodies. The imbalanced relationship between autoreactive T helper and T regulatory cells, activation of TLR in autoreactive B cells and inflammatory cytokines released by Th17 cells are believed to play a pathogenic role in BP [10]. On the other hand, the pathogenic role of autoantibodies to BP180 and BP230 is certain. In this context, tacrolimus (known to act mainly on T cell activation without substantially affecting the humoral immune response)
A
B
C
Figure 1. A) Vesiculobullous eruption with some ulcerated lesions and crusts on the chest of the transplanted patient. Skin biopsy demonstrated a subepidermal vesiculobullous dermatitis (B); direct immunofluorescence revealed IgG and granular C3 at the dermoepidermal junction (C).
383
could provoke an imbalance towards the latter. This phenomenon could explain the unexpected development of an autoimmune disease in an immunosuppressed patient. In a previous report [8], tacrolimus was substituted by mycophenolate (which suppresses both humoral and cell-mediated immunity) with clinical benefit. Our patient could not be treated with mycophenolate because of a previous allergic reaction; azathioprine could be considered as a therapeutic alternative. Disclosure. Financial support: none. Conflict of interest: none. University of Turin, Department of Medical Sciences, v. Cherasco 23, 10126, Torino, Italy
Giovanni CAVALIERE Paolo FAVA Stefania BUSSOLINO Ana Maria MANZIONE Paola SAVOIA
1. Nousari H, Anhalt GJ. Pemphigus and bullous pemphigoid. Lancet 1999; 354: 667-72. 2. Ross EA, Ahmed AR. Bullous pemphigoid-associated nephropathy: report of two cases and review of the literature. Am J Kidney Dis 1989; 14: 225-9. 3. Simon CA, Winkelmann RK. Bullous pemphigoid and glomerulonephritis. Report of four cases. J Am Acad Dermatol 1986; 14: 45663. 4. Chen TJ, Lai PC, Yang LC, Kuo TT, Hong HS. Bullous pemphigoid in a renal transplant recipient: a case report and review of the literature. Am J Clin Dermatol 2009; 10: 197-200. 5. Tessari G, Barba A, Chieregato C, et al. Bullous eruption during chronic renal allograft rejection. Dermatology 2002; 204: 307-8. 6. Davis RF, Ravenscroft J, Hashimoto T, Evans JH, Harman KE. Bullous pemphigoid associated with renal transplant rejection. Clin Exp Dermatol 2011; 36: 824-5. 7. Rodriguez-Caruncho C, Bielsa I, Bayès B, Guinovart R, FernandezFigueras T, Ferrandiz C. Bullous pemphigoid associated with chronic renal allograft rejection: resolution after transplantectomy. J Am Acad Dermatol 2011; 65: e89-90. 8. De Simone C, Caldarola G, Castriota M, Salerno MP, Citterio F. Bullous Pemphigoid in a transplant recipient: is this a sign of allograft rejection? Eur J Dermatol 2011; 22: 280-1. 9. Peruzzo J, Pinheiro Dantas LD, Zampese M. Bullous pemphigoid associated with chronic renal allograft rejection. J Am Acad Dermatol 2013; 68: e192-3. 10. Lo Schiavo A, Ruocco E, Brancaccio G, Caccavale S, Ruocco V, Wolf R. Bullous pemphigoid: etiology, pathogenesis and inducing factors: facts and controversies. Clin Dermatol 2013; 31: 391-9.
identified by searching PubMed and Chinese literature databases (1970-2012). The physical examination of our three cases showed multiple, skin-colored, oval papules, nodules and plaques on their backs (figures 1A-C). Routine laboratory investigations and X-ray of the pelvis and chest were normal. They had no family history of connective tissue nevi. The biopsy of the male patient’s back lesion showed dense, coarse collagen fibers and slightly decreased, fragmented, coarse elastic fibers in the dermis (figures 1D-F) compared to the normal skin (figure 1G-I). Based on the clinical and histopathological findings, the diagnosis of eruptive collagenoma was made for our three cases. No specific treatment wasgiven. In the review of 27 cases, the male to female ratio was 1:1.25. The mean ± SD age at onset was 23.77 ± 17.51 years and the mean time from the onset of lesions to seeing a dermatologist was 7.17 ± 9.73 years. The predisposing factors might include pregnancy, trauma and stress. The rash in one case appeared at a few months of pregnancy, then multiplied and later decreased in size postpartum [1]. Another case had a sudden eruption of eruptive collagenoma after curettage of ‘molluscum contagiosum’ [2]. In one patient, lesions occurred suddenly during a stressful period in her life [3]. Of the 27 patients, 6 (22.2%) cases had skin lesions only on one side of the body (left or right) [2, 4-8], while the other 21 (77.8%) cases had symmetrically distributed lesions. The trunk was the predominant site for eruptive collagenoma (81.2%), followed by the head and neck (29.6%), the upper extremities (29.6%) and the lower extremities (29.6%). Papules were the most common lesions (74.1%), followed by nodules (59.3%) and plaques (25.9%). Lesion sizes less than 1 cm were observed in all cases, lesion sizes ranged from 1- 2 cm in 18.5% and from 2- 3 cm in only 11.1%. Skin-colored lesions were in the majority (81.5%), followed A
B
C
D
E
F
Three cases of eruptive collagenoma and a literature review, 1970-2012
G
H
I
Eruptive collagenoma is a rare dermatosis that is often misdiagnosed as other connective tissue nevi. To date, the literature on eruptive collagenoma is limited. Therefore we summarized and analyzed 27 cases from the world, including 3 cases from our hospital (two women aged respectively 40 and 12 years and a 40-year-old man with a 10-year, 1month and 2-year history of multiple non-tender lesions),
Figure 1. A, B, C) Firm, skin-colored papules, nodules and plaques on the backs of our three cases. D, E) Dense, coarse collagen fibers in the dermis of skin lesion compared to the normal skin (G, H) (H&E, ×100 and ×200). F) Slightly decreased, fragmented and coarse elastic fibers in the dermis of skin lesion compared to the normal skin (I) (Elastic stain ×400).
doi:10.1684/ejd.2014.2316
384
EJD, vol. 24, n◦ 3, May-June 2014
Bullous pemphigoid in a renal transplant recipient Bullous pemphigoid (BP) is a subepidermal autoimmune bullous disease mediated by autoantibodies directed toward antigens (BPAg1-230, BPAg2-180) located in hemidesmosomes and the lamina lucida of the dermal-epidermal junction. BP is usually idiopathic but multiple etiological agents (drugs, physical stimulation, cancers and immune abnormalities) have been identified [1]. We report a 59 yearold kidney-transplant recipient who developed an itchy rash with lichenoid features on the trunk and back nine years post-transplantation. She had undergone hemodialysis from 1998 to 2003 for membranous glomerulonephritis (MGN). In July 2003 she received a cadaveric renal transplant and started an immunosuppressive treatment (tacrolimus 4 mg/d and prednisone 10 mg/d). At the first dermatological visit she did not report any significant comorbidities or other drug intake. Serum creatinine and blood urea nitrogen were 1.2 and 19.6 mg/dL, respectively. Topical and systemic steroids and antihistamines brought a partial clinical benefit, with recurrence at treatment discontinuation. In June 2012, the patient developed bullous lesions on the right breast, initially successfully treated with topical methylprednisolone. After three months new bullous and ulcerated lesions with widespread desquamation on the trunk, upper back and limbs developed (figure 1A). A skin biopsy revealed a subepidermal bulla (figure 1B). Direct immunofluorescence demonstrated IgG and granular C3 deposits at the dermal-epidermal junction (figure 1C). Indirect immunofluorescence showed antibodies binding to the epidermal side of salt-split skin. ELISA testing showed circulating antibodies to BP180 (31 UI/mL) but not to BP230. These findings led to the diagnosis of BP. Positive-emission tomography ruled out an underlying malignancy. Intravenous methylprednisolone (1 mg/kg/d) was started together with oral diamino-diphenyl-sulfone (DDS; 100 mg/d) with a rapid clinical benefit and starting re-epithelialization of the ulcerated lesions. Steroids were gradually tapered to 15 mg/d. One month later, new pruritic bullae appeared on the trunk. Prednisolone was increased to 50 mg/d and then progressively tapered to 15 mg/d. Because of high methaemoglobin blood levels and mild dyspnea, DDS was reduced to 50 mg/d and finally discontinued. At the latest follow-up (December 2013), the cutaneous lesions had completely regressed. EJD, vol. 24, n◦ 3, May-June 2014
BP has rarely been reported associated with renal diseases. Its association with MGN could be due to cross-reactivity to common epitopes present in the cutaneous and renal basement membranes. Renal antigens have never been clearly identified [2] but could be similar to BPAg1 and BPAg2. Some have claimed that BP and MGN represent two distinct manifestations of a generalized autoimmune disorder [3]. BP has been associated with many other autoimmune disorders [4]. A common trigger could be responsible for the development of separate antibodies that attack different antigens in distinct organs. The occurrence of BP in association with renal transplantation is rare; only 11 such cases have been reported [5-9]. Various mechanisms could explain this event. Skin lesions may be caused by acute graft rejection with an immunological cross-reaction between the allograft and the skin. Alternatively, the graft could act as a chronic allogenic stimulus able to induce autoantibodies against antigens of the dermal-epidermal junction. In most cases, the bullous eruption occurred after organ rejection and was often preceded by reduction or withdrawal of immunosuppression. The removal of the allograft was often followed by complete remission [7]. Some authors [8] have hypothesized a causative role of the immunosuppressive drugs. The clinicopathological findings of BP derive from complex interactions between T-cell immunity and B-cell-mediated antibodies. The imbalanced relationship between autoreactive T helper and T regulatory cells, activation of TLR in autoreactive B cells and inflammatory cytokines released by Th17 cells are believed to play a pathogenic role in BP [10]. On the other hand, the pathogenic role of autoantibodies to BP180 and BP230 is certain. In this context, tacrolimus (known to act mainly on T cell activation without substantially affecting the humoral immune response)
A
B
C
Figure 1. A) Vesiculobullous eruption with some ulcerated lesions and crusts on the chest of the transplanted patient. Skin biopsy demonstrated a subepidermal vesiculobullous dermatitis (B); direct immunofluorescence revealed IgG and granular C3 at the dermoepidermal junction (C).
383
could provoke an imbalance towards the latter. This phenomenon could explain the unexpected development of an autoimmune disease in an immunosuppressed patient. In a previous report [8], tacrolimus was substituted by mycophenolate (which suppresses both humoral and cell-mediated immunity) with clinical benefit. Our patient could not be treated with mycophenolate because of a previous allergic reaction; azathioprine could be considered as a therapeutic alternative. Disclosure. Financial support: none. Conflict of interest: none. University of Turin, Department of Medical Sciences, v. Cherasco 23, 10126, Torino, Italy
Giovanni CAVALIERE Paolo FAVA Stefania BUSSOLINO Ana Maria MANZIONE Paola SAVOIA
1. Nousari H, Anhalt GJ. Pemphigus and bullous pemphigoid. Lancet 1999; 354: 667-72. 2. Ross EA, Ahmed AR. Bullous pemphigoid-associated nephropathy: report of two cases and review of the literature. Am J Kidney Dis 1989; 14: 225-9. 3. Simon CA, Winkelmann RK. Bullous pemphigoid and glomerulonephritis. Report of four cases. J Am Acad Dermatol 1986; 14: 45663. 4. Chen TJ, Lai PC, Yang LC, Kuo TT, Hong HS. Bullous pemphigoid in a renal transplant recipient: a case report and review of the literature. Am J Clin Dermatol 2009; 10: 197-200. 5. Tessari G, Barba A, Chieregato C, et al. Bullous eruption during chronic renal allograft rejection. Dermatology 2002; 204: 307-8. 6. Davis RF, Ravenscroft J, Hashimoto T, Evans JH, Harman KE. Bullous pemphigoid associated with renal transplant rejection. Clin Exp Dermatol 2011; 36: 824-5. 7. Rodriguez-Caruncho C, Bielsa I, Bayès B, Guinovart R, FernandezFigueras T, Ferrandiz C. Bullous pemphigoid associated with chronic renal allograft rejection: resolution after transplantectomy. J Am Acad Dermatol 2011; 65: e89-90. 8. De Simone C, Caldarola G, Castriota M, Salerno MP, Citterio F. Bullous Pemphigoid in a transplant recipient: is this a sign of allograft rejection? Eur J Dermatol 2011; 22: 280-1. 9. Peruzzo J, Pinheiro Dantas LD, Zampese M. Bullous pemphigoid associated with chronic renal allograft rejection. J Am Acad Dermatol 2013; 68: e192-3. 10. Lo Schiavo A, Ruocco E, Brancaccio G, Caccavale S, Ruocco V, Wolf R. Bullous pemphigoid: etiology, pathogenesis and inducing factors: facts and controversies. Clin Dermatol 2013; 31: 391-9.
identified by searching PubMed and Chinese literature databases (1970-2012). The physical examination of our three cases showed multiple, skin-colored, oval papules, nodules and plaques on their backs (figures 1A-C). Routine laboratory investigations and X-ray of the pelvis and chest were normal. They had no family history of connective tissue nevi. The biopsy of the male patient’s back lesion showed dense, coarse collagen fibers and slightly decreased, fragmented, coarse elastic fibers in the dermis (figures 1D-F) compared to the normal skin (figure 1G-I). Based on the clinical and histopathological findings, the diagnosis of eruptive collagenoma was made for our three cases. No specific treatment wasgiven. In the review of 27 cases, the male to female ratio was 1:1.25. The mean ± SD age at onset was 23.77 ± 17.51 years and the mean time from the onset of lesions to seeing a dermatologist was 7.17 ± 9.73 years. The predisposing factors might include pregnancy, trauma and stress. The rash in one case appeared at a few months of pregnancy, then multiplied and later decreased in size postpartum [1]. Another case had a sudden eruption of eruptive collagenoma after curettage of ‘molluscum contagiosum’ [2]. In one patient, lesions occurred suddenly during a stressful period in her life [3]. Of the 27 patients, 6 (22.2%) cases had skin lesions only on one side of the body (left or right) [2, 4-8], while the other 21 (77.8%) cases had symmetrically distributed lesions. The trunk was the predominant site for eruptive collagenoma (81.2%), followed by the head and neck (29.6%), the upper extremities (29.6%) and the lower extremities (29.6%). Papules were the most common lesions (74.1%), followed by nodules (59.3%) and plaques (25.9%). Lesion sizes less than 1 cm were observed in all cases, lesion sizes ranged from 1- 2 cm in 18.5% and from 2- 3 cm in only 11.1%. Skin-colored lesions were in the majority (81.5%), followed A
B
C
D
E
F
Three cases of eruptive collagenoma and a literature review, 1970-2012
G
H
I
Eruptive collagenoma is a rare dermatosis that is often misdiagnosed as other connective tissue nevi. To date, the literature on eruptive collagenoma is limited. Therefore we summarized and analyzed 27 cases from the world, including 3 cases from our hospital (two women aged respectively 40 and 12 years and a 40-year-old man with a 10-year, 1month and 2-year history of multiple non-tender lesions),
Figure 1. A, B, C) Firm, skin-colored papules, nodules and plaques on the backs of our three cases. D, E) Dense, coarse collagen fibers in the dermis of skin lesion compared to the normal skin (G, H) (H&E, ×100 and ×200). F) Slightly decreased, fragmented and coarse elastic fibers in the dermis of skin lesion compared to the normal skin (I) (Elastic stain ×400).
doi:10.1684/ejd.2014.2316
384
EJD, vol. 24, n◦ 3, May-June 2014
