Sublethal radionecrosis after prolonged radioscopy: multiple systems issues in interventional cardiology Interventional cardiology procedures have increased over the past few years. In cases of prolonged radioscopy and/or repeated cardiac catheterizations, there is a high risk of acute radiation injury [1]. We report a case of severe cutaneous and muscular radionecrosis after multiple angioplasty procedures, revealing important medical systems issues. A 53-year-old obese man, who was an active smoker and suffered from severe asymptomatic ischemic cardiomyopathy, was admitted to the dermatology department for a necrotic lesion in the right scapular area. Physical examination showed a 10 × 12 cm fibrinous and necrotic ulceration surrounded by an inflammatory and sclerous plaque, measuring 30 × 30 cm (figure 1A). The Magnetic Resonance Imaging showed deep necrosis, reaching the muscles without osteonecrosis of the scapula, and an inflammation signal reaching the mediastinum. Histopathology revealed epidermal ulceration with dermal and hypodermal fibrosis, in accordance with radiodermatitis. Further questioning revealed that the patient had undergone 6 coronarographies with angioplasties (1 to 3 hours per procedure) the year before, for a coronary chronic total occlusion (CCTO) of the circumflex artery. After the fifth coronarography, a cutaneous erosion appeared on the right scapular area, with progressive extension. The French Safety Nuclear Authority estimated a posteriori that the cutaneous irradiation reached 34 to 59 Gy. The investigation revealed: improper settings of the machines, delivering higher doses of radiation than expected; excessive lengths of procedures; failure to take into account the thickness of this obese patient. Finally, physicians failed to identify the initial cutaneous radionecrosis, leading to subsequent irradiations using the same projection. Moreover, revascularization of CCTO was questionable in this patient because of the lack of clear evidence of a potential benefit in this pathology, to be balanced against the high risk of radiodermatitis due to the duration of the procedures [2]. Antifibrotic therapy (vitamin E, pentoxifillin, prednisone, clindamycin) reduced the size of the radionecrosis (figure 1B), helped by surgical excision and grafting 9 months later. Radiodermatitis and radionecrosis are poorly characterized injuries of cardiac catheterizations that may
appear several months or years after a coronarography exposing a patient to a cumulative radiation dose above 10 to 12 Gy [1]. The diagnosis of chronic radiodermatitis following cardiac catheterization essentially relies on clinical findings. The skin lesions encompass a wide spectrum of clinical presentations, from erythema, telangiectasia, atrophy, poikilodermic lesions, sclerosis and pigmentary changes to necrosis, chronic ulceration and epidermoid carcinoma. The lesions have specific localizations, involving the right axillary area or the right dorsal sub-scapular area, depending on the coronary artery explored. Histopathology is not necessary to confirm the diagnosis and usually reveals epidermal ulceration, dermal and hypodermal fibrosis [1, 3]. Radiodermatitis is often misdiagnosed because of the delayed onset of the clinical features. Differential diagnoses include infections, such as cellulitis or ecthyma gangrenosum in cases of inflammatory plaques, morphea in cases of sclerous lesions, or tumors (epidermoid carcinoma, dermatofibrosarcoma). The optimal treatment remains prevention and several recommendations have been established: every procedure must be justified in terms of benefit/risks, the administrated radiation dose should be calculated and recorded in the patients’ medical files for follow-up, as well as the size and the location of the skin exposed, in order to select an alternative projection during future catheterizations, a careful inspection of the exposed skin should be done before each procedure and a systematic long-term follow-up of patients with periodical shoulder and back skin examination should be done because of the delayed consequences of radiation [3, 4]. The usual curative treatment is based on surgical excision of necrotic tissues [1, 3]. In our patient, the lesion was too large and too deep for initial excision. Consequently, we used an original medical treatment combining anti-inflammatory (corticosteroids-antibiotics and clodronate) and an antioxidant combination (pentoxifylline-tocopherol) [5]. This latter treatment enabled the process of established radiationinduced fibroatrophy to be greatly limited by reducing free radical-induced damage [5]. This case of severe radionecrosis illustrates both the multiple dysfunctions in cardiac catheterization procedures that may still exist and the benefit obtained with a medical curative approach using disease modifying agents. Disclosure. Financial support: none. Conflict of interest: none.
1
Department of Dermatology, Department of Radiotherapy, Saint-Louis Hospital, 1 avenue Claude-Vellefaux, 75475 Paris, France 2 Department of Cardiology, Le Raincy-Montfermeil Hospital, France 3
A
B
February 2012
February 2013
Figure 1. Fibrinous and necrotic ulceration of right scapular area, surrounded with an inflammatory and sclerous plaque, measuring 30 × 30 cm (A); evolution after antifibrotic therapy (B).
382
Antoine BADAOUI1 Gentiane MONSEL1 Fabien MONSEL2 Walid AMARA2 Martine BAGOT1 Sylvie DELANIAN3 Manuelle VIGUIER1
1. Vano E, Goicolea J, Galvan C, et al. Skin radiation injuries in patients following repeated coronary angioplasty procedures. Br J Radiol 2001; 74: 1023-31. 2. Shah PB. Management of coronary chronic total occlusion. Circulation 2011; 123: 1780-4. EJD, vol. 24, n◦ 3, May-June 2014
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
appear several months or years after a coronarography exposing a patient to a cumulative radiation dose above 10 to 12 Gy [1]. The diagnosis of chronic radiodermatitis following cardiac catheterization essentially relies on clinical findings. The skin lesions encompass a wide spectrum of clinical presentations, from erythema, telangiectasia, atrophy, poikilodermic lesions, sclerosis and pigmentary changes to necrosis, chronic ulceration and epidermoid carcinoma. The lesions have specific localizations, involving the right axillary area or the right dorsal sub-scapular area, depending on the coronary artery explored. Histopathology is not necessary to confirm the diagnosis and usually reveals epidermal ulceration, dermal and hypodermal fibrosis [1, 3]. Radiodermatitis is often misdiagnosed because of the delayed onset of the clinical features. Differential diagnoses include infections, such as cellulitis or ecthyma gangrenosum in cases of inflammatory plaques, morphea in cases of sclerous lesions, or tumors (epidermoid carcinoma, dermatofibrosarcoma). The optimal treatment remains prevention and several recommendations have been established: every procedure must be justified in terms of benefit/risks, the administrated radiation dose should be calculated and recorded in the patients’ medical files for follow-up, as well as the size and the location of the skin exposed, in order to select an alternative projection during future catheterizations, a careful inspection of the exposed skin should be done before each procedure and a systematic long-term follow-up of patients with periodical shoulder and back skin examination should be done because of the delayed consequences of radiation [3, 4]. The usual curative treatment is based on surgical excision of necrotic tissues [1, 3]. In our patient, the lesion was too large and too deep for initial excision. Consequently, we used an original medical treatment combining anti-inflammatory (corticosteroids-antibiotics and clodronate) and an antioxidant combination (pentoxifylline-tocopherol) [5]. This latter treatment enabled the process of established radiationinduced fibroatrophy to be greatly limited by reducing free radical-induced damage [5]. This case of severe radionecrosis illustrates both the multiple dysfunctions in cardiac catheterization procedures that may still exist and the benefit obtained with a medical curative approach using disease modifying agents. Disclosure. Financial support: none. Conflict of interest: none.
1
Department of Dermatology, Department of Radiotherapy, Saint-Louis Hospital, 1 avenue Claude-Vellefaux, 75475 Paris, France 2 Department of Cardiology, Le Raincy-Montfermeil Hospital, France 3
A
B
February 2012
February 2013
Figure 1. Fibrinous and necrotic ulceration of right scapular area, surrounded with an inflammatory and sclerous plaque, measuring 30 × 30 cm (A); evolution after antifibrotic therapy (B).
382
Antoine BADAOUI1 Gentiane MONSEL1 Fabien MONSEL2 Walid AMARA2 Martine BAGOT1 Sylvie DELANIAN3 Manuelle VIGUIER1
1. Vano E, Goicolea J, Galvan C, et al. Skin radiation injuries in patients following repeated coronary angioplasty procedures. Br J Radiol 2001; 74: 1023-31. 2. Shah PB. Management of coronary chronic total occlusion. Circulation 2011; 123: 1780-4. EJD, vol. 24, n◦ 3, May-June 2014
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
