BJD
British Journal of Dermatology
CASE REPORT
Immunobullous disease and ulcerative colitis: a case series of six patients M.C. Sotiriou,1 C.W. Foo,1 C.T. Scholes2 and J.J. Zone1 1 2
Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Scholes Dermatology, Twin Falls, ID, U.S.A.
Summary Correspondence John J. Zone. E-mail: [email protected]
Accepted for publication 28 March 2015
Funding sources Funding for this publication was provided through the Department of Dermatology at the University of Utah School of Medicine in Salt Lake City, UT, U.S.A.
Conflicts of interest None declared. DOI 10.1111/bjd.13872
Cases of immunobullous skin disease associated with ulcerative colitis (UC) have been previously reported in the literature. There is no clear explanation for this association. In this series, we report six cases of immunobullous disease in patients with UC and discuss potential mechanisms of pathogenesis proposed to explain these concomitant diseases. The clinical presentation, immunopathology and treatment of six new cases are described and analysed. We report six patients, two with linear IgA bullous dermatosis (LABD), one with bullous pemphigoid (BP), one with mucous membrane pemphigoid (MMP) and two with IgA pemphigus. The patients’ ages ranged from 33 to 66 years at the onset of their skin disease, and all but one case had a documented age of UC onset, confirmed with colonoscopy, prior to the development of skin disease. Direct immunofluorescence results in these patients demonstrated IgA basement membrane zone (BMZ) antibodies in the LABD cases, IgG antibodies at the BMZ in the BP and MMP cases, and IgA cell surface antibodies in the patients with IgA pemphigus. Additionally, indirect immunofluorescence was positive in one of the patients with LABD, the patient with BP and both of the patients with IgA pemphigus. The temporal association of UC and skin disease, in addition to the resolution of skin disease with total colectomy in one case, suggests colonic mucosal antigenic stimulation driving immune activation and leading to immunobullous skin disease.
What’s already known about this topic?
• • •
There is a known link between ulcerative colitis and several immunobullous skin diseases. This link between bowel and skin disease is rare, although its prevalence may be more common than previously reported. The exact mechanism is not known, although several hypotheses have been proposed.
What does this study add?
• • •
792
We describe six novel cases of patients with ulcerative colitis and immunobullous skin disease. We report a case where complete remission of skin disease occurred after resection of the inflamed bowel, supporting our theory that the inflamed colon is the source of continuous antigenic stimulation driving the autoimmune response and leading to autoantibody production. The temporal association of the bowel disease preceding the skin disease and remission after colectomy strongly suggest that bowel inflammation initiates the immune response to cutaneous antigens.
British Journal of Dermatology (2015) 173, pp792–796
© 2015 British Association of Dermatologists
Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al. 793
Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disorder that occurs in both adults and children. It is characterized by linear deposition of IgA along the cutaneous basement membrane zone (BMZ). IgA is found to react against 97 and 120 kDa antigens that represent the cleaved ectodomain toward the carboxy terminus of bullous pemphigoid (BP) antigen 180 (BP180/BPAg2).1 BP is also an immunomediated subepidermal vesiculobullous eruption that most commonly occurs in adults. The clinical presentation ranges from early pruritic urticarial lesions to widespread tense bullae. It is characterized by IgG tissue-bound and circulating autoantibodies directed against BP180 (BPAg2) and BP230 (BPAg1).2 The pathogenic IgG antibodies are believed to bind the MCW-1 region of the NC16 domain of BP180.3 IgA pemphigus is a vesiculopustular skin disease associated with neutrophil infiltration, acantholysis, and IgA antibodies against the keratinocyte cell surface, including desmocollin-1, desmoglein-1 and desmoglein-3.4 Ulcerative colitis (UC) is one of two major types of chronic inflammatory bowel disease and affects the large bowel and terminal ileum. The diagnosis of UC is made by colonoscopy, which is characterized by a diffusely erythematous mucosa, with or without ulcerations, extending from the rectum to involve all or part of the large bowel, with no normal intervening mucosa. On histological examination, there is mucosal infiltration of neutrophils in the lamina propria and the crypts forming microabscesses.5 The association of immunobullous disease and UC has been previously reported. In this case series, we describe two cases of LABD, one case of BP, one case of mucous membrane pemphigoid (MMP) and two cases of IgA pemphigus, all with concomitant UC.
Linear IgA bullous dermatosis and ulcerative colitis Case 1 A 45-year-old man with known UC, status postcolectomy with a residual rectal pouch and ileostomy, was referred for ‘folliculitis and impetigo’ 1 year postsurgery. He started developing skin lesions a year prior to his colectomy, when he was hospitalized for UC. The skin lesions had resolved while his UC was being treated with prednisone, but flared shortly after prednisone was discontinued. Initial examination showed erythematous crusted papules over his scalp, eyelids, eyes, chin and chest. He was treated with oral amoxicillin/clavulanic acid for suspected folliculitis with some improvement. He subsequently developed new vesicles and crusted papules. Histology showed subepidermal bullous dermatosis with neutrophils and eosinophils. Direct immunofluorescence (DIF) showed linear BMZ deposition of IgA and fibrinogen in addition to some minimal epithelial cell surface IgA. A diagnosis of LABD was made. The cell surface antibody was of uncertain significance in the absence of acantholysis or an intraepidermal vesicle. Indirect immunofluorescence (IIF) was performed on several occasions and was negative. For the next 4 years he had frequent flares of © 2015 British Association of Dermatologists
papulovesicles that required treatment with dapsone and courses of prednisone. On repeat anoscopy the rectal pouch was noted to be severely inflamed. The rectal pouch was removed and remission of his cutaneous disease ensued within 2 months. Dapsone was gradually tapered and discontinued. He remained clear of cutaneous disease for 3 years of follow-up. Case 2 A 47-year-old woman presented with localized blisters on her arms for 3 years. DIF showed linear IgA deposition along the BMZ. IIF revealed an elevated IgA antibasement antibody titre of 1 : 80 adhering to the epidermal side of split skin. There was no evidence of IgG BMZ antibody on DIF or IIF. She was diagnosed with LABD and started on dapsone. For the following 8 years, her disease was controlled with oral dapsone with infrequent flares. At the age of 58 years, she had a significant increase in frequency of bowel movements with blood and mucus in her stool. She then reported having recurrent episodes of diarrhoea for over 10–20 years. Colonoscopy revealed a pancolitis with ulcerations, consistent with UC. She was started on oral mesalamine for her UC with improvement in her abdominal symptoms. However, due to an intolerance of mesalamine, she preferred treatment with intramuscular triamcinolone injections every 3–4 months. With this treatment, she was asymptomatic for UC. She was kept on oral dapsone for the treatment of her LABD. At age 61 years, she underwent repeat colonoscopy, which continued to show low grade active chronic colitis. Her IIF, after 14 years of LABD, continued to show a BMZ IgA titre of 1 : 80.
Mucous membrane pemphigoid and ulcerative colitis Case 3 A 71-year-old woman with a diagnosis of UC at age 46 years and a previous partial colectomy presented with oral erosions and symblepharon. At the age of 64 years, DIF of a mouth biopsy showed linear deposits of IgG and C3 at the BMZ. She was diagnosed with MMP with ocular involvement. IIF was positive with an IgG BMZ antibody titre of 1 : 20 on monkey oesophagus. Enzyme-linked immunosorbent assay testing for IgG BP180 and BP230 was negative. She was started on dapsone and prednisone but developed severe leukopenia. Her symptoms were then completely controlled with oral mycophenolate mofetil. Attempts to taper mycophenolate mofetil resulted in the recurrence of oral erosions. At 9 years followup, she continued to require mycophenolate mofetil. Her UC remained under moderate control with dietary restriction.
Bullous pemphigoid and ulcerative colitis Case 4 A 66-year-old man developed an increase in frequency of bowel movements. A colonoscopy showed mild colitis of the British Journal of Dermatology (2015) 173, pp792–796
794 Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al.
entire colon and moderately severe diverticulosis. Histopathological examination of a left colonic biopsy showed superficial luminal erosions, crypt loss and distortion. One year later he developed a cutaneous bullous eruption. A skin biopsy showed a subepidermal blister. DIF showed linear IgG and C3 along the BMZ, consistent with BP. He was treated with oral prednisone and mycophenolate mofetil. Three months later he underwent repeat colonoscopy, which showed diffuse colitis involving his entire colon. Multiple biopsies showed diffuse chronic inflammation with cryptitis and crypt abscess formation, which is consistent with UC. Following this finding, he was switched from mycophenolate mofetil to sulfasalazine to manage his pemphigoid and UC but developed severe leukopenia. His pemphigoid continued to be active and resistant to mycophenolate mofetil, azathioprine and plasmapheresis. He was subsequently treated with rituximab and IVIg for resistant skin disease with some improvement. His UC continued to be active.
IgA pemphigus and ulcerative colitis Case 5 A 40-year-old man presented with a new onset of pruritic and painful eruptions on his face, torso, extremities and scalp for 4 days. He reported a history of UC for many years, which was in remission at the time of this new cutaneous eruption. Initial examination of the skin showed erosions with a yellow crust. The skin biopsy was interpreted by general pathology to be consistent with a herpetic infection and he was treated with valaciclovir and trimethoprim–sulfamethoxazole for
secondary infection. He continued to have worsening erosions and vesicles over most of his lower extremities. A viral culture for herpes simplex was negative. A review of the original skin biopsy showed intraepidermal vesicles with neutrophils. DIF was performed and revealed cell surface IgA deposition and linear deposition of IgA along the BMZ. Additionally, IIF on normal human skin revealed IgA cell surface antibody at a titre of 1 : 20. He was diagnosed with IgA pemphigus. He was started on oral prednisone 60 mg daily empirically and his cutaneous eruption cleared. Treatment with prednisone was tapered and he was maintained on dapsone 100 mg daily for maintenance therapy. His UC continued to be active. Case 6 A 28-year-old man presented with erosions on his scalp, gingival and buccal mucosa for several months. A skin biopsy showed features consistent with pemphigus, although DIF also showed minimal granular deposition of IgA and complement in the dermal papillae. IIF was negative for cell surface antibodies. He was initially treated with oral prednisone and oral mycophenolate mofetil and his lesions resolved rapidly. At age 34 years, he presented with recurrence of erosions on his scalp, gingival and buccal mucosa. Repeat histology showed intraepithelial vesicles with acantholysis at all levels of the epithelium and a dense infiltrate of neutrophils with some eosinophils. DIF showed intense grains of IgA on the basal keratinocyte cell surface. A diagnosis of IgA pemphigus was made and he was treated with mycophenolate mofetil and dapsone. At a later date, IIF showed positive IgA cell surface antibodies and the diagnosis of IgA pemphigus was confirmed.
Table 1 Clinical and immunopathological features of six cases of immunobullous disease in patients with ulcerative colitis (UC) Age at diagnosis, years Case
UC
Immunofluorescence
Serology
Skin disease
Sex
Skin disease
Direct
Indirect
BP 180
BP 230
Treatment
1
43
45
M
LABD
IgA CS/BMZ
Neg
ND
ND
2
58a
47
F
LABD
IgA BMZ
ND
ND
3
46
71
F
Mucous membrane pemphigoid
Linear IgG at BMZ, C3
5
2
DDS, MPM
4 5 6
66 SR 36
67 40 34
M M M
BP IgA pemphigus IgA pemphigus
Linear IgG BMZ, C3 IgA CS, BMZ Basal cell surface and weak IgA BMZ
IgA BMZ 1 : 80 (epidermal side of BMZ split skin) IgG BMZ Ab 1 : 20 on monkey oesophagus, negative on BMZ split human skin Neg IgA CS 1 : 20 IgA CS 1 : 10
PDN, DDS, colectomy, rectal resection DDS, TAC
103 ND 8
Neg ND 7
PDN, MPM, PP, RTX PDN, DDS MPM, DDS
BMZ, basement membrane zone; BP, bullous pemphigoid; CS, cell surface; DDS, dapsone; LABD, linear IgA bullous dermatosis; MPM, mycophenolate mofetil; Neg, negative; ND, not done; PDN, prednisone; PP, plasmapheresis; RTX, rituximab; SR, self-reported unknown age; TAC, triamcinolone. aSymptomatic at age 38 years, diagnostic colonoscopy at age 58 years.
British Journal of Dermatology (2015) 173, pp792–796
© 2015 British Association of Dermatologists
Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al. 795
The clinical and immunopathological features of the cases are reviewed in Table 1. These were performed using our standard techniques.1 For many of the patients there are multiple sets of biopsies and serological test results. For this series we report only the patient’s first set of positive results. Five of the six patients had a diagnosis of UC, or symptoms of UC, before the diagnosis of skin disease. Of the two patients with LABD, one had a documented age of diagnosis of UC that preceded the dermatological diagnosis, and one was diagnosed with UC after the LABD diagnosis; however, this patient reported UC symptoms for the previous 20 years. The patients with BP and MMP both had a documented diagnosis of UC prior to their dermatological diagnosis. Of the two patients with IgA pemphigus, one had a past history of UC in remission at the time of presentation, and the other patient’s UC was diagnosed after the dermatological diagnosis. The mean age of dermatological diagnosis was 488 years (range 33–66). Serological tests and DIF studies are summarized in Table 1.
IgA pemphigus. Our sera may not have reacted with colonic epithelium because of relatively low titres of antibodies in patient sera, or it may be that our sera react with antigens other than the putative antigens listed above. Lastly, epitope spreading might occur and explain the reactivity with different antigens. To our knowledge, there have been 16 previously reported cases of LABD associated with UC,10–17 including one that we reported.16 In a series of 70 patients with LABD, five patients had concomitant UC.10 In three previously reported cases (including one reported by us), LABD resolved after colectomy.11,14,16 In our current study, one patient with LABD had resolution of skin disease after complete colectomy. Interestingly, the patients who have not had colectomy continue to have active skin disease requiring treatment. A recent case report by Watchorn et al.18 described a patient with LABD and UC who underwent proctocolectomy and experienced complete resolution of bowel and skin symptoms. Additionally, a literature review by the authors noted three additional cases of total resolution of LABD following proctocolectomy.18 This is strong evidence that UC has a causative effect of the immunobullous skin disease. Colonic involvement in LABD and IgA pemphigus has been reported with positive results of DIF of colonic mucosa, confirming the presence of LABD and pemphigus antigens in the colon.9,19 BP180 is known to be expressed in both the skin and colon.7 In the association between colonic and cutaneous disease, it seems likely that a primary immune response is initiated in inflamed colonic tissue resulting in cross-reactivity with cutaneous BMZ and epidermal cell surface antigens.
Discussion
References
Three years later he was found to have iron deficiency anaemia but claimed no intestinal symptoms. A colonoscopy showed diffuse moderate inflammation with congestion and friability throughout the entire colon and distal proctitis, consistent with UC. He was started on oral mesalamine and azathioprine and his UC remitted. Mycophenolate mofetil was discontinued and he was maintained on oral dapsone. His IgA pemphigus remained clear on dapsone therapy.
Results
We hypothesized that inflammatory bowel-induced inflammation of the intestinal mucosa could be stimulating a humoral immune response to colonic epithelial antigens with subsequent cross-reactivity of antibodies to skin epithelial and basement membrane antigens. This has been described for IgG antibodies to type VII collagen in patients with epidermolysis bullosa acquisita where the presence of IgG antibodies to type VII collagen reacted upon IIF with colonic BMZ.6 We performed further studies on the serum of patients 2, 5 and 6, which had positive IIF on BMZ split human skin substrate. We used normal colon as a substrate for IIF with appropriate fluorescein-conjugated secondary antibodies against gamma chain or alpha chain and could not identify cross-reactivity of colon with the test sera. A known serum containing IgG antibodies against type VII collagen was used as a positive control and it reacted with colonic basement membrane as previously described by Chen et al.6 However, we could not identify reactivity with any of our sera with colonic epithelial antigens. Previous studies have shown that BP180,7 desmoglein-18 and possibly desmoglein-3 are expressed in colonic epithelium.9 Although desmocollin-2 is expressed in normal colon, we can find no reference to desmocollin-1 or desmocollin-3 expression. These are likely antigens in our cases of BP, LABD and © 2015 British Association of Dermatologists
1 Zone JJ, Taylor TB, Kadunce DP, Meyer LJ. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990; 85:812–20. 2 Liu Z, Diaz LA, Troy JL et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest 1993; 92:2480–8. 3 Liu Z, Diaz LA, Giudice GJ. Autoimmune response against the bullous pemphigoid 180 autoantigen. Dermatology 1994; 189(Suppl. 1):34–7. 4 Hashimoto T. Immunopathology of IgA pemphigus. Clin Dermatol 2001; 19:683–9. 5 Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448:427–34. 6 Chen M, O’Toole EA, Sanghavi J et al. The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn’s disease have autoantibodies to type VII collagen. J Invest Dermatol 2002; 118:1059–64. 7 Aho S, Uitto J. 180-kD bullous pemphigoid antigen/type XVII collagen: tissue-specific expression and molecular interactions with keratin 18. J Cell Biochem 1999; 72:356–67. 8 Arnemann J, Spurr NK, Buxton RS. The human gene (DSG3) coding for the pemphigus vulgaris antigen is, like the genes coding for the other two known desmogleins, assigned to chromosome 18. Hum Genet 1992; 89:347–50. British Journal of Dermatology (2015) 173, pp792–796
796 Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al. 9 Bruckner AL, Fitzpatrick JE, Hashimoto T et al. Atypical IgA/IgG pemphigus involving the skin, oral mucosa, and colon in a child: a novel variant of IgA pemphigus? Pediatr Dermatol 2005; 22: 321–7. 10 Paige DG, Leonard JN, Wojnarowska F, Fry L. Linear IgA disease and ulcerative colitis. Br J Dermatol 1997; 136:779–82. 11 Caldarola G, Annese V, Bossa F, Pellicano R. Linear IgA bullous dermatosis and ulcerative colitis treated by proctocolectomy. Eur J Dermatol 2009; 19:651. 12 Taniguchi T, Maejima H, Saito N et al. Case of linear IgA bullous dermatosis-involved ulcerative colitis. Inflamm Bowel Dis 2009; 15:1284–5. 13 Fernandez-Guarino M, Saez EM, Gijon RC et al. Linear IGA dermatosis associated with ulcerative colitis. Eur J Dermatol 2006; 16: 692–3.
British Journal of Dermatology (2015) 173, pp792–796
14 Walker SL, Banerjee P, Harland CC, Black MM. Remission of linear IgA disease associated with ulcerative colitis following panproclocolectomy. Br J Dermatol 2000; 143:1341–2. 15 Chi HI, Arai M. Linear IgA bullous dermatosis associated with ulcerative colitis. J Dermatol 1999; 26:150–3. 16 Egan CA, Meadows KP, Zone JJ. Ulcerative colitis and immunobullous disease cured by colectomy. Arch Dermatol 1999; 135:214–15. 17 De Simone C, Guerriero C, Pellicano R. Linear IgA disease and ulcerative colitis. Eur J Dermatol 1998; 8:48–50. 18 Watchorn RE, Ma S, Gulmann C et al. Linear IgA disease associated with ulcerative colitis: the role of surgery. Clin Exp Dermatol 2014; 39:327–9. 19 Cowan CG, Lamey PJ, Walsh M et al. Linear IgA disease (LAD): immunoglobulin deposition in oral and colonic lesions. J Oral Pathol Med 1995; 24:374–8.
© 2015 British Association of Dermatologists
British Journal of Dermatology
CASE REPORT
Immunobullous disease and ulcerative colitis: a case series of six patients M.C. Sotiriou,1 C.W. Foo,1 C.T. Scholes2 and J.J. Zone1 1 2
Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. Scholes Dermatology, Twin Falls, ID, U.S.A.
Summary Correspondence John J. Zone. E-mail: [email protected]
Accepted for publication 28 March 2015
Funding sources Funding for this publication was provided through the Department of Dermatology at the University of Utah School of Medicine in Salt Lake City, UT, U.S.A.
Conflicts of interest None declared. DOI 10.1111/bjd.13872
Cases of immunobullous skin disease associated with ulcerative colitis (UC) have been previously reported in the literature. There is no clear explanation for this association. In this series, we report six cases of immunobullous disease in patients with UC and discuss potential mechanisms of pathogenesis proposed to explain these concomitant diseases. The clinical presentation, immunopathology and treatment of six new cases are described and analysed. We report six patients, two with linear IgA bullous dermatosis (LABD), one with bullous pemphigoid (BP), one with mucous membrane pemphigoid (MMP) and two with IgA pemphigus. The patients’ ages ranged from 33 to 66 years at the onset of their skin disease, and all but one case had a documented age of UC onset, confirmed with colonoscopy, prior to the development of skin disease. Direct immunofluorescence results in these patients demonstrated IgA basement membrane zone (BMZ) antibodies in the LABD cases, IgG antibodies at the BMZ in the BP and MMP cases, and IgA cell surface antibodies in the patients with IgA pemphigus. Additionally, indirect immunofluorescence was positive in one of the patients with LABD, the patient with BP and both of the patients with IgA pemphigus. The temporal association of UC and skin disease, in addition to the resolution of skin disease with total colectomy in one case, suggests colonic mucosal antigenic stimulation driving immune activation and leading to immunobullous skin disease.
What’s already known about this topic?
• • •
There is a known link between ulcerative colitis and several immunobullous skin diseases. This link between bowel and skin disease is rare, although its prevalence may be more common than previously reported. The exact mechanism is not known, although several hypotheses have been proposed.
What does this study add?
• • •
792
We describe six novel cases of patients with ulcerative colitis and immunobullous skin disease. We report a case where complete remission of skin disease occurred after resection of the inflamed bowel, supporting our theory that the inflamed colon is the source of continuous antigenic stimulation driving the autoimmune response and leading to autoantibody production. The temporal association of the bowel disease preceding the skin disease and remission after colectomy strongly suggest that bowel inflammation initiates the immune response to cutaneous antigens.
British Journal of Dermatology (2015) 173, pp792–796
© 2015 British Association of Dermatologists
Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al. 793
Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disorder that occurs in both adults and children. It is characterized by linear deposition of IgA along the cutaneous basement membrane zone (BMZ). IgA is found to react against 97 and 120 kDa antigens that represent the cleaved ectodomain toward the carboxy terminus of bullous pemphigoid (BP) antigen 180 (BP180/BPAg2).1 BP is also an immunomediated subepidermal vesiculobullous eruption that most commonly occurs in adults. The clinical presentation ranges from early pruritic urticarial lesions to widespread tense bullae. It is characterized by IgG tissue-bound and circulating autoantibodies directed against BP180 (BPAg2) and BP230 (BPAg1).2 The pathogenic IgG antibodies are believed to bind the MCW-1 region of the NC16 domain of BP180.3 IgA pemphigus is a vesiculopustular skin disease associated with neutrophil infiltration, acantholysis, and IgA antibodies against the keratinocyte cell surface, including desmocollin-1, desmoglein-1 and desmoglein-3.4 Ulcerative colitis (UC) is one of two major types of chronic inflammatory bowel disease and affects the large bowel and terminal ileum. The diagnosis of UC is made by colonoscopy, which is characterized by a diffusely erythematous mucosa, with or without ulcerations, extending from the rectum to involve all or part of the large bowel, with no normal intervening mucosa. On histological examination, there is mucosal infiltration of neutrophils in the lamina propria and the crypts forming microabscesses.5 The association of immunobullous disease and UC has been previously reported. In this case series, we describe two cases of LABD, one case of BP, one case of mucous membrane pemphigoid (MMP) and two cases of IgA pemphigus, all with concomitant UC.
Linear IgA bullous dermatosis and ulcerative colitis Case 1 A 45-year-old man with known UC, status postcolectomy with a residual rectal pouch and ileostomy, was referred for ‘folliculitis and impetigo’ 1 year postsurgery. He started developing skin lesions a year prior to his colectomy, when he was hospitalized for UC. The skin lesions had resolved while his UC was being treated with prednisone, but flared shortly after prednisone was discontinued. Initial examination showed erythematous crusted papules over his scalp, eyelids, eyes, chin and chest. He was treated with oral amoxicillin/clavulanic acid for suspected folliculitis with some improvement. He subsequently developed new vesicles and crusted papules. Histology showed subepidermal bullous dermatosis with neutrophils and eosinophils. Direct immunofluorescence (DIF) showed linear BMZ deposition of IgA and fibrinogen in addition to some minimal epithelial cell surface IgA. A diagnosis of LABD was made. The cell surface antibody was of uncertain significance in the absence of acantholysis or an intraepidermal vesicle. Indirect immunofluorescence (IIF) was performed on several occasions and was negative. For the next 4 years he had frequent flares of © 2015 British Association of Dermatologists
papulovesicles that required treatment with dapsone and courses of prednisone. On repeat anoscopy the rectal pouch was noted to be severely inflamed. The rectal pouch was removed and remission of his cutaneous disease ensued within 2 months. Dapsone was gradually tapered and discontinued. He remained clear of cutaneous disease for 3 years of follow-up. Case 2 A 47-year-old woman presented with localized blisters on her arms for 3 years. DIF showed linear IgA deposition along the BMZ. IIF revealed an elevated IgA antibasement antibody titre of 1 : 80 adhering to the epidermal side of split skin. There was no evidence of IgG BMZ antibody on DIF or IIF. She was diagnosed with LABD and started on dapsone. For the following 8 years, her disease was controlled with oral dapsone with infrequent flares. At the age of 58 years, she had a significant increase in frequency of bowel movements with blood and mucus in her stool. She then reported having recurrent episodes of diarrhoea for over 10–20 years. Colonoscopy revealed a pancolitis with ulcerations, consistent with UC. She was started on oral mesalamine for her UC with improvement in her abdominal symptoms. However, due to an intolerance of mesalamine, she preferred treatment with intramuscular triamcinolone injections every 3–4 months. With this treatment, she was asymptomatic for UC. She was kept on oral dapsone for the treatment of her LABD. At age 61 years, she underwent repeat colonoscopy, which continued to show low grade active chronic colitis. Her IIF, after 14 years of LABD, continued to show a BMZ IgA titre of 1 : 80.
Mucous membrane pemphigoid and ulcerative colitis Case 3 A 71-year-old woman with a diagnosis of UC at age 46 years and a previous partial colectomy presented with oral erosions and symblepharon. At the age of 64 years, DIF of a mouth biopsy showed linear deposits of IgG and C3 at the BMZ. She was diagnosed with MMP with ocular involvement. IIF was positive with an IgG BMZ antibody titre of 1 : 20 on monkey oesophagus. Enzyme-linked immunosorbent assay testing for IgG BP180 and BP230 was negative. She was started on dapsone and prednisone but developed severe leukopenia. Her symptoms were then completely controlled with oral mycophenolate mofetil. Attempts to taper mycophenolate mofetil resulted in the recurrence of oral erosions. At 9 years followup, she continued to require mycophenolate mofetil. Her UC remained under moderate control with dietary restriction.
Bullous pemphigoid and ulcerative colitis Case 4 A 66-year-old man developed an increase in frequency of bowel movements. A colonoscopy showed mild colitis of the British Journal of Dermatology (2015) 173, pp792–796
794 Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al.
entire colon and moderately severe diverticulosis. Histopathological examination of a left colonic biopsy showed superficial luminal erosions, crypt loss and distortion. One year later he developed a cutaneous bullous eruption. A skin biopsy showed a subepidermal blister. DIF showed linear IgG and C3 along the BMZ, consistent with BP. He was treated with oral prednisone and mycophenolate mofetil. Three months later he underwent repeat colonoscopy, which showed diffuse colitis involving his entire colon. Multiple biopsies showed diffuse chronic inflammation with cryptitis and crypt abscess formation, which is consistent with UC. Following this finding, he was switched from mycophenolate mofetil to sulfasalazine to manage his pemphigoid and UC but developed severe leukopenia. His pemphigoid continued to be active and resistant to mycophenolate mofetil, azathioprine and plasmapheresis. He was subsequently treated with rituximab and IVIg for resistant skin disease with some improvement. His UC continued to be active.
IgA pemphigus and ulcerative colitis Case 5 A 40-year-old man presented with a new onset of pruritic and painful eruptions on his face, torso, extremities and scalp for 4 days. He reported a history of UC for many years, which was in remission at the time of this new cutaneous eruption. Initial examination of the skin showed erosions with a yellow crust. The skin biopsy was interpreted by general pathology to be consistent with a herpetic infection and he was treated with valaciclovir and trimethoprim–sulfamethoxazole for
secondary infection. He continued to have worsening erosions and vesicles over most of his lower extremities. A viral culture for herpes simplex was negative. A review of the original skin biopsy showed intraepidermal vesicles with neutrophils. DIF was performed and revealed cell surface IgA deposition and linear deposition of IgA along the BMZ. Additionally, IIF on normal human skin revealed IgA cell surface antibody at a titre of 1 : 20. He was diagnosed with IgA pemphigus. He was started on oral prednisone 60 mg daily empirically and his cutaneous eruption cleared. Treatment with prednisone was tapered and he was maintained on dapsone 100 mg daily for maintenance therapy. His UC continued to be active. Case 6 A 28-year-old man presented with erosions on his scalp, gingival and buccal mucosa for several months. A skin biopsy showed features consistent with pemphigus, although DIF also showed minimal granular deposition of IgA and complement in the dermal papillae. IIF was negative for cell surface antibodies. He was initially treated with oral prednisone and oral mycophenolate mofetil and his lesions resolved rapidly. At age 34 years, he presented with recurrence of erosions on his scalp, gingival and buccal mucosa. Repeat histology showed intraepithelial vesicles with acantholysis at all levels of the epithelium and a dense infiltrate of neutrophils with some eosinophils. DIF showed intense grains of IgA on the basal keratinocyte cell surface. A diagnosis of IgA pemphigus was made and he was treated with mycophenolate mofetil and dapsone. At a later date, IIF showed positive IgA cell surface antibodies and the diagnosis of IgA pemphigus was confirmed.
Table 1 Clinical and immunopathological features of six cases of immunobullous disease in patients with ulcerative colitis (UC) Age at diagnosis, years Case
UC
Immunofluorescence
Serology
Skin disease
Sex
Skin disease
Direct
Indirect
BP 180
BP 230
Treatment
1
43
45
M
LABD
IgA CS/BMZ
Neg
ND
ND
2
58a
47
F
LABD
IgA BMZ
ND
ND
3
46
71
F
Mucous membrane pemphigoid
Linear IgG at BMZ, C3
5
2
DDS, MPM
4 5 6
66 SR 36
67 40 34
M M M
BP IgA pemphigus IgA pemphigus
Linear IgG BMZ, C3 IgA CS, BMZ Basal cell surface and weak IgA BMZ
IgA BMZ 1 : 80 (epidermal side of BMZ split skin) IgG BMZ Ab 1 : 20 on monkey oesophagus, negative on BMZ split human skin Neg IgA CS 1 : 20 IgA CS 1 : 10
PDN, DDS, colectomy, rectal resection DDS, TAC
103 ND 8
Neg ND 7
PDN, MPM, PP, RTX PDN, DDS MPM, DDS
BMZ, basement membrane zone; BP, bullous pemphigoid; CS, cell surface; DDS, dapsone; LABD, linear IgA bullous dermatosis; MPM, mycophenolate mofetil; Neg, negative; ND, not done; PDN, prednisone; PP, plasmapheresis; RTX, rituximab; SR, self-reported unknown age; TAC, triamcinolone. aSymptomatic at age 38 years, diagnostic colonoscopy at age 58 years.
British Journal of Dermatology (2015) 173, pp792–796
© 2015 British Association of Dermatologists
Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al. 795
The clinical and immunopathological features of the cases are reviewed in Table 1. These were performed using our standard techniques.1 For many of the patients there are multiple sets of biopsies and serological test results. For this series we report only the patient’s first set of positive results. Five of the six patients had a diagnosis of UC, or symptoms of UC, before the diagnosis of skin disease. Of the two patients with LABD, one had a documented age of diagnosis of UC that preceded the dermatological diagnosis, and one was diagnosed with UC after the LABD diagnosis; however, this patient reported UC symptoms for the previous 20 years. The patients with BP and MMP both had a documented diagnosis of UC prior to their dermatological diagnosis. Of the two patients with IgA pemphigus, one had a past history of UC in remission at the time of presentation, and the other patient’s UC was diagnosed after the dermatological diagnosis. The mean age of dermatological diagnosis was 488 years (range 33–66). Serological tests and DIF studies are summarized in Table 1.
IgA pemphigus. Our sera may not have reacted with colonic epithelium because of relatively low titres of antibodies in patient sera, or it may be that our sera react with antigens other than the putative antigens listed above. Lastly, epitope spreading might occur and explain the reactivity with different antigens. To our knowledge, there have been 16 previously reported cases of LABD associated with UC,10–17 including one that we reported.16 In a series of 70 patients with LABD, five patients had concomitant UC.10 In three previously reported cases (including one reported by us), LABD resolved after colectomy.11,14,16 In our current study, one patient with LABD had resolution of skin disease after complete colectomy. Interestingly, the patients who have not had colectomy continue to have active skin disease requiring treatment. A recent case report by Watchorn et al.18 described a patient with LABD and UC who underwent proctocolectomy and experienced complete resolution of bowel and skin symptoms. Additionally, a literature review by the authors noted three additional cases of total resolution of LABD following proctocolectomy.18 This is strong evidence that UC has a causative effect of the immunobullous skin disease. Colonic involvement in LABD and IgA pemphigus has been reported with positive results of DIF of colonic mucosa, confirming the presence of LABD and pemphigus antigens in the colon.9,19 BP180 is known to be expressed in both the skin and colon.7 In the association between colonic and cutaneous disease, it seems likely that a primary immune response is initiated in inflamed colonic tissue resulting in cross-reactivity with cutaneous BMZ and epidermal cell surface antigens.
Discussion
References
Three years later he was found to have iron deficiency anaemia but claimed no intestinal symptoms. A colonoscopy showed diffuse moderate inflammation with congestion and friability throughout the entire colon and distal proctitis, consistent with UC. He was started on oral mesalamine and azathioprine and his UC remitted. Mycophenolate mofetil was discontinued and he was maintained on oral dapsone. His IgA pemphigus remained clear on dapsone therapy.
Results
We hypothesized that inflammatory bowel-induced inflammation of the intestinal mucosa could be stimulating a humoral immune response to colonic epithelial antigens with subsequent cross-reactivity of antibodies to skin epithelial and basement membrane antigens. This has been described for IgG antibodies to type VII collagen in patients with epidermolysis bullosa acquisita where the presence of IgG antibodies to type VII collagen reacted upon IIF with colonic BMZ.6 We performed further studies on the serum of patients 2, 5 and 6, which had positive IIF on BMZ split human skin substrate. We used normal colon as a substrate for IIF with appropriate fluorescein-conjugated secondary antibodies against gamma chain or alpha chain and could not identify cross-reactivity of colon with the test sera. A known serum containing IgG antibodies against type VII collagen was used as a positive control and it reacted with colonic basement membrane as previously described by Chen et al.6 However, we could not identify reactivity with any of our sera with colonic epithelial antigens. Previous studies have shown that BP180,7 desmoglein-18 and possibly desmoglein-3 are expressed in colonic epithelium.9 Although desmocollin-2 is expressed in normal colon, we can find no reference to desmocollin-1 or desmocollin-3 expression. These are likely antigens in our cases of BP, LABD and © 2015 British Association of Dermatologists
1 Zone JJ, Taylor TB, Kadunce DP, Meyer LJ. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990; 85:812–20. 2 Liu Z, Diaz LA, Troy JL et al. A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest 1993; 92:2480–8. 3 Liu Z, Diaz LA, Giudice GJ. Autoimmune response against the bullous pemphigoid 180 autoantigen. Dermatology 1994; 189(Suppl. 1):34–7. 4 Hashimoto T. Immunopathology of IgA pemphigus. Clin Dermatol 2001; 19:683–9. 5 Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007; 448:427–34. 6 Chen M, O’Toole EA, Sanghavi J et al. The epidermolysis bullosa acquisita antigen (type VII collagen) is present in human colon and patients with Crohn’s disease have autoantibodies to type VII collagen. J Invest Dermatol 2002; 118:1059–64. 7 Aho S, Uitto J. 180-kD bullous pemphigoid antigen/type XVII collagen: tissue-specific expression and molecular interactions with keratin 18. J Cell Biochem 1999; 72:356–67. 8 Arnemann J, Spurr NK, Buxton RS. The human gene (DSG3) coding for the pemphigus vulgaris antigen is, like the genes coding for the other two known desmogleins, assigned to chromosome 18. Hum Genet 1992; 89:347–50. British Journal of Dermatology (2015) 173, pp792–796
796 Immunobullous disease and ulcerative colitis, M.C. Sotiriou et al. 9 Bruckner AL, Fitzpatrick JE, Hashimoto T et al. Atypical IgA/IgG pemphigus involving the skin, oral mucosa, and colon in a child: a novel variant of IgA pemphigus? Pediatr Dermatol 2005; 22: 321–7. 10 Paige DG, Leonard JN, Wojnarowska F, Fry L. Linear IgA disease and ulcerative colitis. Br J Dermatol 1997; 136:779–82. 11 Caldarola G, Annese V, Bossa F, Pellicano R. Linear IgA bullous dermatosis and ulcerative colitis treated by proctocolectomy. Eur J Dermatol 2009; 19:651. 12 Taniguchi T, Maejima H, Saito N et al. Case of linear IgA bullous dermatosis-involved ulcerative colitis. Inflamm Bowel Dis 2009; 15:1284–5. 13 Fernandez-Guarino M, Saez EM, Gijon RC et al. Linear IGA dermatosis associated with ulcerative colitis. Eur J Dermatol 2006; 16: 692–3.
British Journal of Dermatology (2015) 173, pp792–796
14 Walker SL, Banerjee P, Harland CC, Black MM. Remission of linear IgA disease associated with ulcerative colitis following panproclocolectomy. Br J Dermatol 2000; 143:1341–2. 15 Chi HI, Arai M. Linear IgA bullous dermatosis associated with ulcerative colitis. J Dermatol 1999; 26:150–3. 16 Egan CA, Meadows KP, Zone JJ. Ulcerative colitis and immunobullous disease cured by colectomy. Arch Dermatol 1999; 135:214–15. 17 De Simone C, Guerriero C, Pellicano R. Linear IgA disease and ulcerative colitis. Eur J Dermatol 1998; 8:48–50. 18 Watchorn RE, Ma S, Gulmann C et al. Linear IgA disease associated with ulcerative colitis: the role of surgery. Clin Exp Dermatol 2014; 39:327–9. 19 Cowan CG, Lamey PJ, Walsh M et al. Linear IgA disease (LAD): immunoglobulin deposition in oral and colonic lesions. J Oral Pathol Med 1995; 24:374–8.
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