Case Report Received: January 8, 2015 Accepted after revision: May 1, 2015 Published online: June 16, 2015
Dermatology 2015;231:112–115 DOI: 10.1159/000431172
Linear IgA Bullous Dermatosis Secondary to Infliximab Therapy in a Patient with Ulcerative Colitis Jochen Hoffmann a Eva Hadaschik a Alexander Enk a Wolfgang Stremmel b Annika Gauss b
Departments of a Dermatology and b Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
Key Words Linear IgA bullous dermatosis, drug-induced · Infliximab · ‘Paradoxical’ autoimmune reaction · Ulcerative colitis · Anti-tumor necrosis factor-α
Abstract Linear IgA bullous disease (LABD) is a rare vesiculobullous autoimmune skin disorder whose etiology and pathogenesis are not completely understood. Its occurrence has been related to malignancies, inflammatory diseases and several drugs. This report describes a 49-year-old Caucasian male with a 14-year history of ulcerative colitis who received infliximab to treat the refractory course of his bowel disease. During induction therapy with infliximab, he developed LABD. Treatment with infliximab was discontinued, and the skin lesions were successfully treated with oral steroids and dapsone. Considering the close chronological relation between administration of the tumor necrosis factor-α inhibitor and onset of the skin disease, we hypothesize that this is the first reported case of infliximab-induced LABD. Similar to psoriasis, it may represent a ‘paradoxical’ autoimmune reaction triggered by anti-tumor necrosis factor-α therapy. © 2015 S. Karger AG, Basel
Introduction
Linear IgA bullous dermatosis (LABD), or linear IgA disease, is a rare acquired autoimmune vesiculobullous disease, which presents with clinical characteristics that overlap with bullous pemphigoid and dermatitis herpetiformis [1–3]. Its diagnostic immunopathological feature, visible by direct immunofluorescence, is the presence of linear deposits of IgA along the basement membrane zone of the epidermis [4]. The pathogenesis involves IgA and, less frequently, IgG autoantibodies directed against antigens at the basement membrane zone, consecutive complement activation, a predominantly neutrophilic inflammatory infiltration, and the production of proinflammatory cytokines triggered by the antigen-antibody reaction [5–7]. In adults, gastrointestinal diseases, malignant tumors, infections, and several medications have previously been linked to the occurrence of LABD. However, evidence is limited to case reports and small case series [5, 6]. Inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC), are most frequently reported among the associated gastrointestinal diseases [6, 8–10]. Various medications have been suspected as potential triggers. The
© 2015 S. Karger AG, Basel 1018–8665/15/2312–0112$39.50/0 E-Mail [email protected] www.karger.com/drm
majority of reports implicate vancomycin as the causal agent, with a time lag between onset of therapy and occurrence of the first visible skin lesions of 24 h to 15 days [3, 4, 11]. Thus far, there is no published case report considering infliximab (IFX) or another tumor necrosis factor-α (TNF-α) inhibitor as the inducing agent of LABD. However, there is one case report each of a bullous pemphigoid and a pemphigus foliaceus developing under antiTNF-α therapy [12]. LABD can usually be successfully treated using dapsone with or without oral steroids [6]. We report for the first time a case in which a patient with UC developed LABD after initiation of IFX therapy. Case Report
The patient is a Caucasian male who was initially diagnosed with left-sided UC at the age of 35 years. The disease developed a steroid-dependent course, and oral mesalamine as well as common local therapies such as mesalamine enemas and budesonide foam were no longer sufficiently effective. Therefore, at age 47, the patient was started on azathioprine at a dose of 2.3 mg/kg body weight in addition
Dr. Annika Gauss Department of Gastroenterology, University Hospital Heidelberg Im Neuenheimer Feld 410 DE–69120 Heidelberg (Germany) E-Mail annika.gauss @ med.uni-heidelberg.de
Downloaded by: University of Hong Kong 198.143.53.2 - 1/27/2016 1:24:17 PM
Color version available online
Fig. 1. Endoscopic images at different sites of the rectal and sigmoid mucosa prior to IFX
Color version available online
therapy, showing features of severe inflammation with erythema, friability and profuse fibrin exudates.
a
b
c
Fig. 2. a Annular tense bullae on the patient’s forearm. b, c Rapid generalization of annular expanding plaques and bullae within 3 days of the first contact at the Department of Dermatology.
LABD Induced by Infliximab
duced recently. Regarding his UC, the patient did not notice any therapeutic effect of IFX. An urgent dermatological consult was requested. The patient presented with sparsely scattered tense annular bullae on the left forearm, both thighs, and the trunk (fig. 2a). The mucous membranes were not affected. Skin biopsies were taken for hematoxylin and eosin staining and direct immunofluorescence. Serum autoantibodies were determined. Since the patient at the time of the first dermatological consult presented limited disease without systemic symptoms, topical treatment was started until further diagnostic results were available. In the meantime, the annular vesiculobullous lesions spread over the entire body within the following 3 days, accompanied by intense pruritus and pain (fig. 2b, c). The analysis of serum antibodies, including ANA, ENA, dsDNA, BP180, BP230, desmoglein 1, desmoglein 3, and collagen VII antibodies, yielded negative
results except for an ANA titer of 1: 320. Conventional histology showed subepidermal blister formation with a predominantly neutrophilic infiltrate (fig. 3). Direct immunofluorescence demonstrated strong linear IgA-dominant immunoglobulin deposits along the basement membrane zone (fig. 4). These findings strongly supported the clinical diagnosis of LABD. Because the patient had not received any other new medication, and the skin lesions had appeared within a few weeks of beginning IFX therapy, the TNF-α inhibitor was strongly suspected to be the causal agent. IFX therapy was discontinued. Upon worsening cutaneous symptoms, the patient was started on systemic prednisone at 100 mg per day, dapsone at 100 mg per day, and supportive topical treatment as an inpatient. On this regimen, no new bullae formed, and existent lesions began to heal within a week, resulting in a reduction of the prednisone dose to 70 mg per day. During follow-up visits, the skin lesions continuously im-
Dermatology 2015;231:112–115 DOI: 10.1159/000431172
113
Downloaded by: University of Hong Kong 198.143.53.2 - 1/27/2016 1:24:17 PM
to oral mesalamine at a dose of 1.5 g per day. On this regimen, he was in clinical remission for about 1 year, but soon experienced a loss of response. A colonoscopy performed 19 months after initiation of azathioprine treatment showed severe inflammation with fibrin exudates and ulcerations in the rectum and sigmoid colon (fig. 1). Cytomegalovirus infection was excluded in a rectal biopsy, and bacterial infections were ruled out by stool analysis. Concurrent with azathioprine treatment, intravenous IFX was started at a dose of 5 mg/kg body weight at weeks 0, 2 and 6. Seven days after the third IFX infusion, the patient called the IBD outpatient clinic to report newly developed vesicular skin lesions all over his body. When prompted, he remembered that he had previously noticed a single vesicle on the abdominal skin about 3 weeks after the second IFX infusion. The concomitant treatment at that time consisted of azathioprine, oral mesalamine, rectal budesonide, calcium, and vitamin D, none of which had been intro-
Color version available online
Color version available online
a
b
Fig. 3. Skin biopsy showing subepidermal cleavage with a predominantly neutrophilic in-
Fig. 4. Direct immunofluorescence from a
flammatory infiltrate (lower back). Hematoxylin and eosin. a ×2.5; b ×40.
perilesional area demonstrating linear IgA deposits at the dermoepidermal junction (lower back).
Discussion
To the best of our knowledge, this represents the first reported case of a patient developing LABD related to IFX therapy.
114
The medical history of our patient reveals two possible causes of LABD. The first and most obvious cause is the patient’s UC, which has been previously identified as a risk factor for LABD in several case reports [6, 9, 10]. Regarding the pathogenesis of LABD in UC, Yamada et al. [6] suggest that severe damage to the intestinal epithelial barrier and the resulting exposure of the basement membrane lead to an excessive immune response against both foreign and self-antigens of the intestinal tract, inducing the production of IgA antibodies against cutaneous antigens [13, 14]. Our patient had been suffering from UC for 14 years when the skin lesions first appeared. His UC was active at the onset of LABD, presenting as a long-term flare-up with bloody diarrhea. The long course of the patient’s bowel disease prior to the presentation of his skin lesions does not rule out UC as a trigger of LABD as other extraintestinal manifestations, such as primary sclerosing cholangitis [15], pyoderma gangrenosum [16] or pulmonary involvement [17], have been reported years after the first diagnosis of IBD. However, it appears more likely that the patient developed LABD as a consequence of the IFX infusions due to the chronology of the onset of skin lesions in tandem with the start of IFX therapy. Soon after the second infusion, the patient noticed a single vesicle, and multiple disseminated bullous lesions occurred after the third infusion. The time lag may be explained by the rising concentrations of IFX in the patient’s body accumulating during induction therapy. IFX or other anti-TNF-α agents have not been previously described as triggers of
Dermatology 2015;231:112–115 DOI: 10.1159/000431172
LABD. In fact, anti-TNF-α treatment has been successfully used in some cases of autoimmune bullous skin disorder [18–22]. One case report describes a young woman with a long history of UC and associated LABD whose gut inflammation and skin lesions could not be treated with steroids, but responded to IFX [6]. This does not prove an inherent therapeutic effect of anti-TNF-α in LABD as the regeneration of the intestinal epithelial barrier induced by IFX may have been responsible for the beneficial effect on the LABD in that case. Other case reports link the development and exacerbation of the autoimmune bullous dermatoses pemphigus foliaceus, bullous pemphigoid [12] and dermatitis herpetiformis [23] to previous TNF-α antagonist treatment. The ‘paradoxical’ development of autoimmune diseases under TNF-targeted therapies has been described before with psoriasis vulgaris, which can be successfully treated, but also triggered by antiTNF-α treatment in some patients with IBD or arthritis [24, 25]. The pathophysiology of these unexpected side effects is not fully understood. One hypothesis that may explain the development of autoimmune diseases under anti-TNF-α treatment is an increased production of interferon-α by plasmacytoid dendritic cells following TNF-α blockade, as TNF-α normally inhibits plasmacytoid dendritic cell maturation from hematopoietic progenitors as well as interferon-α production [26, 27]. Furthermore, TNF-α neutralization was shown to deplete cytotoxic T cells, which normally contribute to peripheral immune tolerance by suppressing autoreactive B cells [28].
Hoffmann/Hadaschik/Enk/Stremmel/ Gauss
Downloaded by: University of Hong Kong 198.143.53.2 - 1/27/2016 1:24:17 PM
proved, eventually presenting as dry erythematous maculae without the formation of new bullae. As a result, the steroid dose was further reduced to 50 mg per day after 2 weeks and then tapered by 10 mg per day every 4 weeks until a daily dose of 30 mg. Thereafter, it was decreased by 5 mg per day every 4 weeks until a stable dose of 5 mg per day. The dose of dapsone was reduced to 50 mg per day 7 weeks after its initiation due to epigastric pain interpreted as side effect. At the patient’s visit 15 months after onset of the skin lesions, the skin had cleared except for a slight postinflammatory hyperpigmentation at the previously active sites, so that the dose of prednisone was reduced from 10 to 5 mg per day, while dapsone treatment was continued. At the patient’s most recent visit 18 months after onset of the skin lesions, no new lesions were reported and dapsone therapy was discontinued. Regarding the patient’s UC, it has been stable with oral mesalamine at 4.5 g per day and low-dose cortisone. He reported 2–4 bowel movements per day without blood. Due to its lack of therapeutic effect, azathioprine treatment was discontinued. The most recent measurement of fecal calprotectin yielded a concentration of 203 μg/g (normal:
Dermatology 2015;231:112–115 DOI: 10.1159/000431172
Linear IgA Bullous Dermatosis Secondary to Infliximab Therapy in a Patient with Ulcerative Colitis Jochen Hoffmann a Eva Hadaschik a Alexander Enk a Wolfgang Stremmel b Annika Gauss b
Departments of a Dermatology and b Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
Key Words Linear IgA bullous dermatosis, drug-induced · Infliximab · ‘Paradoxical’ autoimmune reaction · Ulcerative colitis · Anti-tumor necrosis factor-α
Abstract Linear IgA bullous disease (LABD) is a rare vesiculobullous autoimmune skin disorder whose etiology and pathogenesis are not completely understood. Its occurrence has been related to malignancies, inflammatory diseases and several drugs. This report describes a 49-year-old Caucasian male with a 14-year history of ulcerative colitis who received infliximab to treat the refractory course of his bowel disease. During induction therapy with infliximab, he developed LABD. Treatment with infliximab was discontinued, and the skin lesions were successfully treated with oral steroids and dapsone. Considering the close chronological relation between administration of the tumor necrosis factor-α inhibitor and onset of the skin disease, we hypothesize that this is the first reported case of infliximab-induced LABD. Similar to psoriasis, it may represent a ‘paradoxical’ autoimmune reaction triggered by anti-tumor necrosis factor-α therapy. © 2015 S. Karger AG, Basel
Introduction
Linear IgA bullous dermatosis (LABD), or linear IgA disease, is a rare acquired autoimmune vesiculobullous disease, which presents with clinical characteristics that overlap with bullous pemphigoid and dermatitis herpetiformis [1–3]. Its diagnostic immunopathological feature, visible by direct immunofluorescence, is the presence of linear deposits of IgA along the basement membrane zone of the epidermis [4]. The pathogenesis involves IgA and, less frequently, IgG autoantibodies directed against antigens at the basement membrane zone, consecutive complement activation, a predominantly neutrophilic inflammatory infiltration, and the production of proinflammatory cytokines triggered by the antigen-antibody reaction [5–7]. In adults, gastrointestinal diseases, malignant tumors, infections, and several medications have previously been linked to the occurrence of LABD. However, evidence is limited to case reports and small case series [5, 6]. Inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC), are most frequently reported among the associated gastrointestinal diseases [6, 8–10]. Various medications have been suspected as potential triggers. The
© 2015 S. Karger AG, Basel 1018–8665/15/2312–0112$39.50/0 E-Mail [email protected] www.karger.com/drm
majority of reports implicate vancomycin as the causal agent, with a time lag between onset of therapy and occurrence of the first visible skin lesions of 24 h to 15 days [3, 4, 11]. Thus far, there is no published case report considering infliximab (IFX) or another tumor necrosis factor-α (TNF-α) inhibitor as the inducing agent of LABD. However, there is one case report each of a bullous pemphigoid and a pemphigus foliaceus developing under antiTNF-α therapy [12]. LABD can usually be successfully treated using dapsone with or without oral steroids [6]. We report for the first time a case in which a patient with UC developed LABD after initiation of IFX therapy. Case Report
The patient is a Caucasian male who was initially diagnosed with left-sided UC at the age of 35 years. The disease developed a steroid-dependent course, and oral mesalamine as well as common local therapies such as mesalamine enemas and budesonide foam were no longer sufficiently effective. Therefore, at age 47, the patient was started on azathioprine at a dose of 2.3 mg/kg body weight in addition
Dr. Annika Gauss Department of Gastroenterology, University Hospital Heidelberg Im Neuenheimer Feld 410 DE–69120 Heidelberg (Germany) E-Mail annika.gauss @ med.uni-heidelberg.de
Downloaded by: University of Hong Kong 198.143.53.2 - 1/27/2016 1:24:17 PM
Color version available online
Fig. 1. Endoscopic images at different sites of the rectal and sigmoid mucosa prior to IFX
Color version available online
therapy, showing features of severe inflammation with erythema, friability and profuse fibrin exudates.
a
b
c
Fig. 2. a Annular tense bullae on the patient’s forearm. b, c Rapid generalization of annular expanding plaques and bullae within 3 days of the first contact at the Department of Dermatology.
LABD Induced by Infliximab
duced recently. Regarding his UC, the patient did not notice any therapeutic effect of IFX. An urgent dermatological consult was requested. The patient presented with sparsely scattered tense annular bullae on the left forearm, both thighs, and the trunk (fig. 2a). The mucous membranes were not affected. Skin biopsies were taken for hematoxylin and eosin staining and direct immunofluorescence. Serum autoantibodies were determined. Since the patient at the time of the first dermatological consult presented limited disease without systemic symptoms, topical treatment was started until further diagnostic results were available. In the meantime, the annular vesiculobullous lesions spread over the entire body within the following 3 days, accompanied by intense pruritus and pain (fig. 2b, c). The analysis of serum antibodies, including ANA, ENA, dsDNA, BP180, BP230, desmoglein 1, desmoglein 3, and collagen VII antibodies, yielded negative
results except for an ANA titer of 1: 320. Conventional histology showed subepidermal blister formation with a predominantly neutrophilic infiltrate (fig. 3). Direct immunofluorescence demonstrated strong linear IgA-dominant immunoglobulin deposits along the basement membrane zone (fig. 4). These findings strongly supported the clinical diagnosis of LABD. Because the patient had not received any other new medication, and the skin lesions had appeared within a few weeks of beginning IFX therapy, the TNF-α inhibitor was strongly suspected to be the causal agent. IFX therapy was discontinued. Upon worsening cutaneous symptoms, the patient was started on systemic prednisone at 100 mg per day, dapsone at 100 mg per day, and supportive topical treatment as an inpatient. On this regimen, no new bullae formed, and existent lesions began to heal within a week, resulting in a reduction of the prednisone dose to 70 mg per day. During follow-up visits, the skin lesions continuously im-
Dermatology 2015;231:112–115 DOI: 10.1159/000431172
113
Downloaded by: University of Hong Kong 198.143.53.2 - 1/27/2016 1:24:17 PM
to oral mesalamine at a dose of 1.5 g per day. On this regimen, he was in clinical remission for about 1 year, but soon experienced a loss of response. A colonoscopy performed 19 months after initiation of azathioprine treatment showed severe inflammation with fibrin exudates and ulcerations in the rectum and sigmoid colon (fig. 1). Cytomegalovirus infection was excluded in a rectal biopsy, and bacterial infections were ruled out by stool analysis. Concurrent with azathioprine treatment, intravenous IFX was started at a dose of 5 mg/kg body weight at weeks 0, 2 and 6. Seven days after the third IFX infusion, the patient called the IBD outpatient clinic to report newly developed vesicular skin lesions all over his body. When prompted, he remembered that he had previously noticed a single vesicle on the abdominal skin about 3 weeks after the second IFX infusion. The concomitant treatment at that time consisted of azathioprine, oral mesalamine, rectal budesonide, calcium, and vitamin D, none of which had been intro-
Color version available online
Color version available online
a
b
Fig. 3. Skin biopsy showing subepidermal cleavage with a predominantly neutrophilic in-
Fig. 4. Direct immunofluorescence from a
flammatory infiltrate (lower back). Hematoxylin and eosin. a ×2.5; b ×40.
perilesional area demonstrating linear IgA deposits at the dermoepidermal junction (lower back).
Discussion
To the best of our knowledge, this represents the first reported case of a patient developing LABD related to IFX therapy.
114
The medical history of our patient reveals two possible causes of LABD. The first and most obvious cause is the patient’s UC, which has been previously identified as a risk factor for LABD in several case reports [6, 9, 10]. Regarding the pathogenesis of LABD in UC, Yamada et al. [6] suggest that severe damage to the intestinal epithelial barrier and the resulting exposure of the basement membrane lead to an excessive immune response against both foreign and self-antigens of the intestinal tract, inducing the production of IgA antibodies against cutaneous antigens [13, 14]. Our patient had been suffering from UC for 14 years when the skin lesions first appeared. His UC was active at the onset of LABD, presenting as a long-term flare-up with bloody diarrhea. The long course of the patient’s bowel disease prior to the presentation of his skin lesions does not rule out UC as a trigger of LABD as other extraintestinal manifestations, such as primary sclerosing cholangitis [15], pyoderma gangrenosum [16] or pulmonary involvement [17], have been reported years after the first diagnosis of IBD. However, it appears more likely that the patient developed LABD as a consequence of the IFX infusions due to the chronology of the onset of skin lesions in tandem with the start of IFX therapy. Soon after the second infusion, the patient noticed a single vesicle, and multiple disseminated bullous lesions occurred after the third infusion. The time lag may be explained by the rising concentrations of IFX in the patient’s body accumulating during induction therapy. IFX or other anti-TNF-α agents have not been previously described as triggers of
Dermatology 2015;231:112–115 DOI: 10.1159/000431172
LABD. In fact, anti-TNF-α treatment has been successfully used in some cases of autoimmune bullous skin disorder [18–22]. One case report describes a young woman with a long history of UC and associated LABD whose gut inflammation and skin lesions could not be treated with steroids, but responded to IFX [6]. This does not prove an inherent therapeutic effect of anti-TNF-α in LABD as the regeneration of the intestinal epithelial barrier induced by IFX may have been responsible for the beneficial effect on the LABD in that case. Other case reports link the development and exacerbation of the autoimmune bullous dermatoses pemphigus foliaceus, bullous pemphigoid [12] and dermatitis herpetiformis [23] to previous TNF-α antagonist treatment. The ‘paradoxical’ development of autoimmune diseases under TNF-targeted therapies has been described before with psoriasis vulgaris, which can be successfully treated, but also triggered by antiTNF-α treatment in some patients with IBD or arthritis [24, 25]. The pathophysiology of these unexpected side effects is not fully understood. One hypothesis that may explain the development of autoimmune diseases under anti-TNF-α treatment is an increased production of interferon-α by plasmacytoid dendritic cells following TNF-α blockade, as TNF-α normally inhibits plasmacytoid dendritic cell maturation from hematopoietic progenitors as well as interferon-α production [26, 27]. Furthermore, TNF-α neutralization was shown to deplete cytotoxic T cells, which normally contribute to peripheral immune tolerance by suppressing autoreactive B cells [28].
Hoffmann/Hadaschik/Enk/Stremmel/ Gauss
Downloaded by: University of Hong Kong 198.143.53.2 - 1/27/2016 1:24:17 PM
proved, eventually presenting as dry erythematous maculae without the formation of new bullae. As a result, the steroid dose was further reduced to 50 mg per day after 2 weeks and then tapered by 10 mg per day every 4 weeks until a daily dose of 30 mg. Thereafter, it was decreased by 5 mg per day every 4 weeks until a stable dose of 5 mg per day. The dose of dapsone was reduced to 50 mg per day 7 weeks after its initiation due to epigastric pain interpreted as side effect. At the patient’s visit 15 months after onset of the skin lesions, the skin had cleared except for a slight postinflammatory hyperpigmentation at the previously active sites, so that the dose of prednisone was reduced from 10 to 5 mg per day, while dapsone treatment was continued. At the patient’s most recent visit 18 months after onset of the skin lesions, no new lesions were reported and dapsone therapy was discontinued. Regarding the patient’s UC, it has been stable with oral mesalamine at 4.5 g per day and low-dose cortisone. He reported 2–4 bowel movements per day without blood. Due to its lack of therapeutic effect, azathioprine treatment was discontinued. The most recent measurement of fecal calprotectin yielded a concentration of 203 μg/g (normal:
