Case Report Received: April 2, 2013 Accepted after revision: August 27, 2013 Published online: November 19, 2013
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
Association of Linear IgA Bullous Disease with Ulcerative Colitis: A Case of Successful Treatment with Infliximab S. Yamada T. Makino M. Jinnin K. Sakai S. Fukushima Y. Inoue H. Ihn Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
Abstract Linear IgA bullous disease (LABD) has been reported in association with inflammatory bowel disease, in particular ulcerative colitis (UC). We reporting a 34-year-old female who developed LABD during a flare-up of UC. We administered infliximab, which has been approved for the treatment of UC; infliximab dramatically improved the cutaneous lesions and bowel symptoms. This is the first report showing a marked effect of infliximab on LABD. First, we hypothesize that infliximab works for UC and then calms down excessive production of inflammatory cytokines and autoantibodies, and so stricter control of UC by infliximab is beneficial against the skin condition of LABD. Second, we suggest that TNF-α production in the lesion of LABD is increased, so TNF-α plays an important role in developing cutaneous lesions. This case suggests that infliximab, a monoclonal antibody against TNF-α, is efficacious in the cutaneous symptoms of LABD. © 2013 S. Karger AG, Basel
Introduction
Linear IgA bullous disease (LABD) is a rare subepidermal autoimmune bullous disease characterized by linear deposits of
IgA at the dermoepidermal junction [1, 2]. The exact pathogenesis has been related to IgA and IgG autoantibodies directed against various antigens at the basement membrane zone, the antigen-antibody reaction and complement activation inducing lymphocyte and neutrophil migration, and the production of inflammatory cytokines. LABD has been reported in association with various diseases, in particular malignant lymphoma, other carcinomas, autoimmune diseases or inflammatory bowel diseases (IBDs) [3]. For treatment, dapsone and/or low-dose corticosteroid have been effective. We report the case of a patient who developed LABD whilst receiving treatment for ulcerative colitis (UC) and recovered remarkably after initiation of infliximab. Case Report
A 34-year-old female was referred to our department. She had been diagnosed as having UC 15 years before. She was receiving oral sulfasalazine at 3,000 mg daily and prednisolone at alternately 5 and 7.5 mg daily. Five months before the first visit, she had low fever, then she noticed pruritic erythematous macules and papules on the trunk 3 months later. The eruption spread gradually, and the itch became more intense. At the same time she also developed an UC relapse, with severe diarrhea and bloody stool. She visited a nearby dermato-
© 2013 S. Karger AG, Basel 1018–8665/13/2274–0295$38.00/0 E-Mail [email protected] www.karger.com/drm
logical clinic and was prescribed a topical corticosteroid, however her eruption did not improve and she developed erosions and pustules. A bullous disorder was considered and she was referred to our clinic. Her past medical history included Takayasu’s arteritis 13 years previously. She was receiving oral ciclosporin 50 mg daily, and her disease activity was well controlled. On physical examination, there were numerous erythematous patches with erosions, pustules and crusting on her trunk, buttocks and lower extremities. There was post-inflammatory hyperpigmentation. There were no mucosal lesions. Laboratory tests showed an increased leukocyte count of 10,700/μl (neutrophils 9,630/μl). C-reactive protein level (1.65 mg/dl), serum amyloid A level (34.9 μg/ml) and IgA level (470 mg/dl) were also increased. Neither antinuclear antibody nor antibody against BP180 were present. Other biochemical tests were within normal limits. Histological examination showed hyperkeratosis, acanthosis and liquefactive degeneration just below the basal epidermal layer. There were perivascular infiltrations of inflammatory cells such as lymphocytes, neutrophils, histiocytes and eosinophils in the upper dermis. There were neutrophil aggregations and debris near the liquefactive degeneration in the upper dermis (fig. 1). Direct immunofluorescence (DF) studies showed linear IgA and C3 deposits at
Dr. Saori Yamada Department of Dermatology and Plastic Surgery Faculty of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 (Japan) E-Mail saoritinkerbell @ gmail.com
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
Key Words Linear IgA bullous disease · Ulcerative colitis · Infliximab · TNF-α
Color version available online
1.0 mm
×100
b
500 μm
×200
1 Color version available online
a
b
Color version available online
2
Fig. 1. Hematoxylin and eosin staining of the skin eruption. Histological examination showed hyperkeratosis, acanthosis and liquefactive degeneration just below the basal epidermal layer. a Perivascular infiltrations of inflammatory cells. b Neutrophil aggregations and debris near the liquefactive degeneration in partial upper dermis. Fig. 2. DF (a) and IIF using salt split of normal skin (b). a DF showed linear IgA deposits at the dermoepidermal junction. b IIF revealed linear C3 deposits on the epidermal side. Fig. 3. Endoscopic findings. Endoscopy revealed erythema, friability of the mucosa and superficial ulceration.
296
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
3
Yamada/Makino/Jinnin/Sakai/ Fukushima/Inoue/Ihn
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
a
Color version available online
a
b
Fig. 4. Cutaneous lesions of abdomen before (a) and 1 month after infliximab (b). By treatment with infliximab, the erosions epithelial-
ized and the eruptions became pigmented.
Discussion
IBD has been reported in association with various extra-intestinal diseases. There are a number of reports of IBD associated with autoimmune blistering diseases. Interestingly, in most cases the diag-
Linear IgA Bullous Disease and Ulcerative Colitis Treated with Infliximab
nosis of IBD predated the development of the skin condition [5]. The breakdown of the intestinal epithelial layer and exposure of the mucosal basement membrane in IBD might result in an excessive immune response against both foreign and autologous antigens of the intestinal tract. This might trigger the production of IgA antibodies directed against cutaneous antigens such as BP180 and collagen VII, and lead to the production of specific bullous disorders [5, 6]. LABD might result from the presentation of multiple target antigens according to this hypothetical mechanism. The association between IBD and autoimmune blistering diseases has been described most frequently for LABD, even though it is the rarest of these diseases [5]. This might be due to the fact that the most important mucosal responses to antigens are IgA responses and that excessive IgA secretion also occurs in IBD [5, 7]. IgA antibodies are produced in the germinal center of Peyer’s patches, which are lymphoid tissue collections in the small intestine, and secreted on the luminal surface of the intestinal epithelial cells. In our patient, LABD was associated with a flare-up of UC. However, the appearance of LABD has not been reported to correspond to the disease activity of UC in other reports of this association [8]. We hypothesize that it is the chronic duration of UC that leads to the development of LABD. Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody directed against TNF-α, which has been approved
for the treatment of immune-mediated inflammatory disorders, including rheumatoid arthritis, Crohn’s disease, psoriasis and UC. Etanercept, another TNF-blocking agent, has been reported to be effective in other bullous diseases, such as cicatricial pemphigoid [9] and pemphigus vulgaris [10]. Conversely, anti-TNF-α agents have been reported to induce autoimmune bullous diseases [11]. This might be considered another example of a paradoxical reaction, as has been described in the case of psoriasis [12]. This is the first report on infliximab having a marked effect on LABD. This might be due to a direct action on UC, as in the report of Caldarola et al. [13]. An alternative or complementary mechanism of action of infliximab might be directly antagonizing the increased levels of TNF-α present in LABD, as reported by Caproni et al. [14]. This case report suggests that TNF-α might play an important role in the development of LABD, thus explaining the therapeutic efficacy of infliximab. Future studies might provide support for this hypothesis. Disclosure Statement
The authors report no conflicts of interest.
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
297
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
the dermoepidermal junction, but the indirect immunofluorescence (IIF) test was negative. IIF performed using salt split of normal human skin revealed linear IgA and C3 deposits on the epidermal side (fig. 2). Based on these studies, the patient was diagnosed as having LABD. We suspected that her disease had become worse and resistant to treatments because the eruptions developed in spite of taking prednisolone. At first, she was treated with dapsone 50 mg daily, without increasing the dose of prednisolone. She had severe abdominal symptoms (Lichtiger’s clinical activity index = 13) [4], so she underwent colonoscopy. The endoscopic result was consistent with severe UC (fig. 3). Treatment with infliximab (5 mg/kg), started for her UC, dramatically improved the cutaneous lesions in a few days (fig. 4). The eruptions cleared and itching was reduced. The outbreak of blisters resolved. After a week, the itching disappeared, the erosions epithelialized, and the eruption resolved leaving post-inflammatory hyperpigmentation. Also, her bowel symptoms disappeared (Lichtiger’s clinical activity index = 3) [4]. She continues on infliximab and the rash remains quiescent.
References
298
6 Taniguchi T, Maejima H, Saito N, Katsuoka K, Haruki S: Case of linear IgA bullous dermatosis-involved ulcerative colitis. Inflamm Bowel Dis 2009;15:1284–1285. 7 Birnie AJ, Perkins W: A case of linear IgA disease occurring in a patient with colonic Crohn’s disease. Br J Dermatol 2005; 153: 1050–1052. 8 Paige DG, Leonard JN, Wojnarowska F, Fry L: Linear IgA disease and ulcerative colitis. Br J Dermatol 1997;136:779–782. 9 Kennedy JS, Devillez RL, Henning JS: Recalcitrant cicatricial pemphigoid treated with the anti-TNF-alpha agent etanercept. J Drugs Dermatol 2010;9:68–70. 10 Shetty A, Marcum CB, Glass LF, Carter JD: Successful treatment of pemphigus vulgaris with etanercept in four patients. J Drugs Dermatol 2009;8:940–943.
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
11 Boussemart L, Jacobelli S, Batteux F, Goulvestre C, Grange P, Carlotti A, Morini JP, Gorin I, Ziza JM, Avril MF, Dupin N: Autoimmune bullous skin diseases occurring under antitumor necrosis factor therapy: two case reports. Dermatology 2010;221:201–205. 12 Ko JM, Gottlieb AB, Kerbleski JF: Induction and exacerbation of psoriasis with TNFblockade therapy: a review and analysis of 127 cases. J Dermatolog Treat 2009;20:100–108. 13 Caldarola G, Annese V, Bossa F, Pellicano R: Linear IgA bullous dermatosis and ulcerative colitis treated by proctocolectomy. Eur J Dermatol 2009;19:651. 14 Caproni M, Rolfo S, Bernacchi E, Bianchi B, Brazzini B, Fabbri P: The role of lymphocytes, granulocytes, mast cells and their related cytokines in lesional skin of linear IgA bullous dermatosis. Br J Dermatol 1999; 140: 1072– 1078.
Yamada/Makino/Jinnin/Sakai/ Fukushima/Inoue/Ihn
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
1 Nanda A, Dvorak R, Al-Sabah H, Madda JP, Anim JT, Alsaleh QA: Association of linear IgA bullous disease of childhood with Crohn’s disease. Int J Dermatol 2006;45:1184–1186. 2 Torres T, Sanches M, Selores M: Linear IgA bullous disease in a patient with Crohn’s disease. Acta Dermatovenerol Alp Panonica Adriat 2010;19:29–31. 3 Sandoval M, Farias MM, Gonzalez S: Linear IgA bullous dermatosis: report of five cases in Chile. Int J Dermatol 2012;51:1303–1306. 4 Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–1845. 5 Shipman AR, Reddy H, Wojnarowska F: Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review. Clin Exp Dermatol 2012;37:461–468.
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
Association of Linear IgA Bullous Disease with Ulcerative Colitis: A Case of Successful Treatment with Infliximab S. Yamada T. Makino M. Jinnin K. Sakai S. Fukushima Y. Inoue H. Ihn Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
Abstract Linear IgA bullous disease (LABD) has been reported in association with inflammatory bowel disease, in particular ulcerative colitis (UC). We reporting a 34-year-old female who developed LABD during a flare-up of UC. We administered infliximab, which has been approved for the treatment of UC; infliximab dramatically improved the cutaneous lesions and bowel symptoms. This is the first report showing a marked effect of infliximab on LABD. First, we hypothesize that infliximab works for UC and then calms down excessive production of inflammatory cytokines and autoantibodies, and so stricter control of UC by infliximab is beneficial against the skin condition of LABD. Second, we suggest that TNF-α production in the lesion of LABD is increased, so TNF-α plays an important role in developing cutaneous lesions. This case suggests that infliximab, a monoclonal antibody against TNF-α, is efficacious in the cutaneous symptoms of LABD. © 2013 S. Karger AG, Basel
Introduction
Linear IgA bullous disease (LABD) is a rare subepidermal autoimmune bullous disease characterized by linear deposits of
IgA at the dermoepidermal junction [1, 2]. The exact pathogenesis has been related to IgA and IgG autoantibodies directed against various antigens at the basement membrane zone, the antigen-antibody reaction and complement activation inducing lymphocyte and neutrophil migration, and the production of inflammatory cytokines. LABD has been reported in association with various diseases, in particular malignant lymphoma, other carcinomas, autoimmune diseases or inflammatory bowel diseases (IBDs) [3]. For treatment, dapsone and/or low-dose corticosteroid have been effective. We report the case of a patient who developed LABD whilst receiving treatment for ulcerative colitis (UC) and recovered remarkably after initiation of infliximab. Case Report
A 34-year-old female was referred to our department. She had been diagnosed as having UC 15 years before. She was receiving oral sulfasalazine at 3,000 mg daily and prednisolone at alternately 5 and 7.5 mg daily. Five months before the first visit, she had low fever, then she noticed pruritic erythematous macules and papules on the trunk 3 months later. The eruption spread gradually, and the itch became more intense. At the same time she also developed an UC relapse, with severe diarrhea and bloody stool. She visited a nearby dermato-
© 2013 S. Karger AG, Basel 1018–8665/13/2274–0295$38.00/0 E-Mail [email protected] www.karger.com/drm
logical clinic and was prescribed a topical corticosteroid, however her eruption did not improve and she developed erosions and pustules. A bullous disorder was considered and she was referred to our clinic. Her past medical history included Takayasu’s arteritis 13 years previously. She was receiving oral ciclosporin 50 mg daily, and her disease activity was well controlled. On physical examination, there were numerous erythematous patches with erosions, pustules and crusting on her trunk, buttocks and lower extremities. There was post-inflammatory hyperpigmentation. There were no mucosal lesions. Laboratory tests showed an increased leukocyte count of 10,700/μl (neutrophils 9,630/μl). C-reactive protein level (1.65 mg/dl), serum amyloid A level (34.9 μg/ml) and IgA level (470 mg/dl) were also increased. Neither antinuclear antibody nor antibody against BP180 were present. Other biochemical tests were within normal limits. Histological examination showed hyperkeratosis, acanthosis and liquefactive degeneration just below the basal epidermal layer. There were perivascular infiltrations of inflammatory cells such as lymphocytes, neutrophils, histiocytes and eosinophils in the upper dermis. There were neutrophil aggregations and debris near the liquefactive degeneration in the upper dermis (fig. 1). Direct immunofluorescence (DF) studies showed linear IgA and C3 deposits at
Dr. Saori Yamada Department of Dermatology and Plastic Surgery Faculty of Life Sciences, Kumamoto University 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556 (Japan) E-Mail saoritinkerbell @ gmail.com
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
Key Words Linear IgA bullous disease · Ulcerative colitis · Infliximab · TNF-α
Color version available online
1.0 mm
×100
b
500 μm
×200
1 Color version available online
a
b
Color version available online
2
Fig. 1. Hematoxylin and eosin staining of the skin eruption. Histological examination showed hyperkeratosis, acanthosis and liquefactive degeneration just below the basal epidermal layer. a Perivascular infiltrations of inflammatory cells. b Neutrophil aggregations and debris near the liquefactive degeneration in partial upper dermis. Fig. 2. DF (a) and IIF using salt split of normal skin (b). a DF showed linear IgA deposits at the dermoepidermal junction. b IIF revealed linear C3 deposits on the epidermal side. Fig. 3. Endoscopic findings. Endoscopy revealed erythema, friability of the mucosa and superficial ulceration.
296
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
3
Yamada/Makino/Jinnin/Sakai/ Fukushima/Inoue/Ihn
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
a
Color version available online
a
b
Fig. 4. Cutaneous lesions of abdomen before (a) and 1 month after infliximab (b). By treatment with infliximab, the erosions epithelial-
ized and the eruptions became pigmented.
Discussion
IBD has been reported in association with various extra-intestinal diseases. There are a number of reports of IBD associated with autoimmune blistering diseases. Interestingly, in most cases the diag-
Linear IgA Bullous Disease and Ulcerative Colitis Treated with Infliximab
nosis of IBD predated the development of the skin condition [5]. The breakdown of the intestinal epithelial layer and exposure of the mucosal basement membrane in IBD might result in an excessive immune response against both foreign and autologous antigens of the intestinal tract. This might trigger the production of IgA antibodies directed against cutaneous antigens such as BP180 and collagen VII, and lead to the production of specific bullous disorders [5, 6]. LABD might result from the presentation of multiple target antigens according to this hypothetical mechanism. The association between IBD and autoimmune blistering diseases has been described most frequently for LABD, even though it is the rarest of these diseases [5]. This might be due to the fact that the most important mucosal responses to antigens are IgA responses and that excessive IgA secretion also occurs in IBD [5, 7]. IgA antibodies are produced in the germinal center of Peyer’s patches, which are lymphoid tissue collections in the small intestine, and secreted on the luminal surface of the intestinal epithelial cells. In our patient, LABD was associated with a flare-up of UC. However, the appearance of LABD has not been reported to correspond to the disease activity of UC in other reports of this association [8]. We hypothesize that it is the chronic duration of UC that leads to the development of LABD. Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody directed against TNF-α, which has been approved
for the treatment of immune-mediated inflammatory disorders, including rheumatoid arthritis, Crohn’s disease, psoriasis and UC. Etanercept, another TNF-blocking agent, has been reported to be effective in other bullous diseases, such as cicatricial pemphigoid [9] and pemphigus vulgaris [10]. Conversely, anti-TNF-α agents have been reported to induce autoimmune bullous diseases [11]. This might be considered another example of a paradoxical reaction, as has been described in the case of psoriasis [12]. This is the first report on infliximab having a marked effect on LABD. This might be due to a direct action on UC, as in the report of Caldarola et al. [13]. An alternative or complementary mechanism of action of infliximab might be directly antagonizing the increased levels of TNF-α present in LABD, as reported by Caproni et al. [14]. This case report suggests that TNF-α might play an important role in the development of LABD, thus explaining the therapeutic efficacy of infliximab. Future studies might provide support for this hypothesis. Disclosure Statement
The authors report no conflicts of interest.
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
297
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
the dermoepidermal junction, but the indirect immunofluorescence (IIF) test was negative. IIF performed using salt split of normal human skin revealed linear IgA and C3 deposits on the epidermal side (fig. 2). Based on these studies, the patient was diagnosed as having LABD. We suspected that her disease had become worse and resistant to treatments because the eruptions developed in spite of taking prednisolone. At first, she was treated with dapsone 50 mg daily, without increasing the dose of prednisolone. She had severe abdominal symptoms (Lichtiger’s clinical activity index = 13) [4], so she underwent colonoscopy. The endoscopic result was consistent with severe UC (fig. 3). Treatment with infliximab (5 mg/kg), started for her UC, dramatically improved the cutaneous lesions in a few days (fig. 4). The eruptions cleared and itching was reduced. The outbreak of blisters resolved. After a week, the itching disappeared, the erosions epithelialized, and the eruption resolved leaving post-inflammatory hyperpigmentation. Also, her bowel symptoms disappeared (Lichtiger’s clinical activity index = 3) [4]. She continues on infliximab and the rash remains quiescent.
References
298
6 Taniguchi T, Maejima H, Saito N, Katsuoka K, Haruki S: Case of linear IgA bullous dermatosis-involved ulcerative colitis. Inflamm Bowel Dis 2009;15:1284–1285. 7 Birnie AJ, Perkins W: A case of linear IgA disease occurring in a patient with colonic Crohn’s disease. Br J Dermatol 2005; 153: 1050–1052. 8 Paige DG, Leonard JN, Wojnarowska F, Fry L: Linear IgA disease and ulcerative colitis. Br J Dermatol 1997;136:779–782. 9 Kennedy JS, Devillez RL, Henning JS: Recalcitrant cicatricial pemphigoid treated with the anti-TNF-alpha agent etanercept. J Drugs Dermatol 2010;9:68–70. 10 Shetty A, Marcum CB, Glass LF, Carter JD: Successful treatment of pemphigus vulgaris with etanercept in four patients. J Drugs Dermatol 2009;8:940–943.
Dermatology 2013;227:295–298 DOI: 10.1159/000355354
11 Boussemart L, Jacobelli S, Batteux F, Goulvestre C, Grange P, Carlotti A, Morini JP, Gorin I, Ziza JM, Avril MF, Dupin N: Autoimmune bullous skin diseases occurring under antitumor necrosis factor therapy: two case reports. Dermatology 2010;221:201–205. 12 Ko JM, Gottlieb AB, Kerbleski JF: Induction and exacerbation of psoriasis with TNFblockade therapy: a review and analysis of 127 cases. J Dermatolog Treat 2009;20:100–108. 13 Caldarola G, Annese V, Bossa F, Pellicano R: Linear IgA bullous dermatosis and ulcerative colitis treated by proctocolectomy. Eur J Dermatol 2009;19:651. 14 Caproni M, Rolfo S, Bernacchi E, Bianchi B, Brazzini B, Fabbri P: The role of lymphocytes, granulocytes, mast cells and their related cytokines in lesional skin of linear IgA bullous dermatosis. Br J Dermatol 1999; 140: 1072– 1078.
Yamada/Makino/Jinnin/Sakai/ Fukushima/Inoue/Ihn
Downloaded by: James Cook University 137.219.5.13 - 8/26/2017 3:57:43 PM
1 Nanda A, Dvorak R, Al-Sabah H, Madda JP, Anim JT, Alsaleh QA: Association of linear IgA bullous disease of childhood with Crohn’s disease. Int J Dermatol 2006;45:1184–1186. 2 Torres T, Sanches M, Selores M: Linear IgA bullous disease in a patient with Crohn’s disease. Acta Dermatovenerol Alp Panonica Adriat 2010;19:29–31. 3 Sandoval M, Farias MM, Gonzalez S: Linear IgA bullous dermatosis: report of five cases in Chile. Int J Dermatol 2012;51:1303–1306. 4 Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–1845. 5 Shipman AR, Reddy H, Wojnarowska F: Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review. Clin Exp Dermatol 2012;37:461–468.
