Clinical dermatology • Review article
Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review
Conflict of interest: none declared.
Dr Alexa R. Shipman, Department of Medicine, Norfolk and Norwich NHS Trust, Norwich, UK
We report two patients with subepidermal autoimmune blistering diseases and inflammatory bowel disease (IBD) [one with linear IgA disease (LAD) and ulcerative colitis (UC), and the other with mucous membrane pemphigoid (MMP) and Crohn disease (CD)], and present a review of all previously reported cases. We reviewed the literature, and found 48 cases of patients with autoimmune blistering diseases and IBD. The blistering diseases were LAD (25 patients), bullous pemphigoid (BP) (21), MMP (1) and pemphigoid gestationis (1), while the IBD types comprised UC (40) and CD (8). We describe the clinical and immunopathological features and demographic characteristics of the patients. In all but one case, the diagnosis of IBD predated the development of the skin condition. The association was more common with LAD than BP. The immunopathogenesis of IBD and autoimmune blistering diseases is discussed and a link between them hypothesized, namely, that the presentation of multiple antigens to the immune system during the unregulated inflammation in the bowel wall results in excitation of the immune system and recognition of autologous antigens.
The subepidermal autoimmune blistering disease linear IgA disease (LAD) and the pemphigoid group [bullous pemphigoid (BP), pemphigoid gestationis (PG) and mucous membrane pemphigoid (MMP)] are mediated by autoantibodies to basement-membrane proteins,1,2 and share the target antigens BP180 (collagen XVII) and BP230 (BPAG1). BP is the most common blistering disease, with an incidence in Europe of 6–30 cases per million people per year. LAD, PG and MMP are much rarer, with incidences of < 0.5, 0.5 and 1–2 per million per year, respectively.3–6 Although LAD and the pemphigoid group are autoimmune diseases, associations of LAD and BP with other autoimmune diseases are rare, whereas this is less rare with PG7 and MMP.8 There is documented association between BP and neurological disease (dementia, cerebrovascular disease and multiple sclerosis9–12), possibly due to crossreactivity between the BP180 and BP230 isoforms expressed in brain and skin.13,14 The subepidermal blistering disease epidermolysis acquisita, which is mediated by autoantibodies to collagen VII, is associated with inflammatory bowel disease (IBD), and this has been ascribed to crossreactivity of antibodies with collagen VII in skin and gut; such antibodies are found in Crohn’s disease (CD).15–17
Two patients presented to our bullous disease clinic with co-existing blistering disease and IBD, prompting us to re-evaluate the case reports of these associations to determine if there were shared clinical features that might provide clues to the mechanism of this association.
The patients both attended the Oxford bullous disease clinic, which acts as a secondary referral centre. Immunofluorescence (IMF) and immunoblotting were performed for both patients, as previously described.18
The first patient (designated case 17 in Table 1) was a 38-year-old man, who had been diagnosed with UC. Two years later, he was admitted with diarrhoea, abdominal pain, anaemia and fever. He received blood transfusions and 30 mg prednisolone, but developed a sagittal sinus thrombosis. He was started on phenytoin, heparin and warfarin, but required a colectomy and ileostomy soon after. His postoperative recovery was complicated by blistering on his back and chest, and a biopsy was taken. Direct IMF showed linear IgA at the dermoepidermal junction, and although indirect IMF was negative, immunoblotting identified antibodies to a 130 kDa protein (possibly BP180 shed ectodomain with IgA) and BP180 (IgG), consistent with a diagnosis of LAD. The patient was started on dapsone. His skin condition responded and he later went into remission off treatment; however, he required a further proctectomy and formation of an ileal–anal pouch to control his UC.
Table 1. Summary of case reports of patients with ulcerative colitis (UC) and linear IgA disease (LAD).
|120||M||12||20||Yes||IgA, IgG, IgM, C3||IgA||ND||PDN, SSZ||DDS, SMO||Colon cancer|
|220||M||36||41||Yes||IgA||Negative||ND||ASA, PDN||PDN, AZT|| |
|320||M||52||60||Yes||IgA||IgA||ND||SSZ, PDN||PDN, SMO, SSZ|| |
|420||F||30||38||Yes||IgA, IgM||Negative||ND||SSZ||DDS, SMO||Colon cancer|
|520||M||59||60||No||IgA, (C3)*||Positive||ND|| ||PDN, AZT, DDS|| |
|620||F||21||64||No||IgA, (C3)*||Positive||ND||PDN||DDS|| |
|720||F||7||8||Yes||IgA||Positive||ND||PDN, ASA||DDS, SMO|| |
|1022||F||30||41||–||IgA||–||ND|| || || |
|1123||F||30||43||Yes||IgA||IgA||ND||PDN, AZT||PDN|| |
|1324||M||54||54||No||IgA||IgA||ND|| ||DDS, PDN, ASA||Renal cancer|
|1426||F||27||28||No||IgA||IgA||ND||ASA, PDN|| || |
|1527||F||10||12||Yes||IgA, C3||Negative||ND||PDN, SSZ||PDN, Cs, THD|| |
|1628||M||60||64|| ||IgA||–||ND|| || || |
|1729||M||23||24||Yes||IgA|| ||120 kDa|| ||DDS, ASA, AZT, colectomy|| |
|1830||M||36||48||Yes||IgA, C3|| ||210 kDa||PDN, AZT||DDS, PDN|| |
|1931||F||18||31||Yes||IgA||IgA||97 kDa|| ||DDS, colectomy|| |
|20*||M||38||40||No||IgA||Negative||180 kDa||PDN, SSZ||DDS|| |
The second patient was a 16-year-old girl (the previously reported case 819 in Table 4), who presented with abdominal pain and altered bowel habit, simultaneously with painful eyes, photophobia, mouth ulcers, bleeding gums, dysphagia and dysuria. She was diagnosed as having CD. A biopsy was taken from her lip. Direct IMF showed linear staining for IGG and C3 at the basement membrane zone (BMZ). Indirect IMF showed circulating IgG anti-BMZ antibodies binding to the dermal side of split skin. Immunoblotting identified IgG antibodies to the BP180 antigen, leading to a diagnosis of MMP. The patient was treated with a number of medications including potent topical steroids, cyclophosphamide, prednisolone, dapsone, mycophenolate mofetil, minocycline and nicotinamide. However, the disease progressed, causing gingivitis, oropharyngeal blisters and strictures, vulval erosions, a blistering eruption, mainly over her limbs, and ocular scarring with entropion and trichiasis, which required surgery. She was started on infliximab 200 mg weekly in combination with prednisolone and azathioprine, which resulted in a dramatic improvement, and her disease remains well controlled.
The literature on the association of subepidermal autoimmune blistering disease, LAD and the pemphigoid group (BP, PG and MMP) with IBD (namely UC and CD), was searched using PubMed, the data extracted into tables and evaluated for demographic, clinical and immunopathological features. Papers that failed to specify the gastrointestinal (GI) diagnosis were not included.
The clinical and immunopathological features of the cases and their demographics, reported by us and the literature, are shown in Tables 1–5. In total, 48 cases of patients with these autoimmune blistering diseases and IBD were found in the literature: the blistering diseases were LAD (25 patients,) BP (21), MMP (1) and PG (1), and the IBD comprised UC (40) and CD (8).
Table 2. Summary of case reports of patients with ulcerative colitis (UC) and bullous pemphigoid (BP).
|132||M||NK||40||–||IgG, C3||–||ND||ASA||PDN|| |
|434||F||75||75||No||IgG, C3||–||ND||SSZ||PDN|| |
|535||M||17||20||–||C3||IgG, C3||180 kDa||–||DDS|| |
|635||M||41||51||–||C3||IgG, C3||200 kDa, 220 kDa||AZT, DDS, IVIg||PDN, Cs||GBS, hypothyroid|
|736||M||62||69||Yes||–||–||ND||SSZ||PDN, AZT||Cervical myelopathy|
|837||F||45||51||Yes||IgG, IgM, C3||Positive||ND||SSZ||PDN, SSZ|| |
|937||M||24||44||No||IgM, C3||Positive||ND||SSZ||PDN||MS, HA|
|1037||F||37||45||Yes||IgG, C3||Positive||ND||SSZ, PDN||–||Thyrotoxicity|
|1137||M||19||27||No||IgG, C3||Positive||ND||SSZ, PDN||PDN, AZT||Hypothyroid, GM|
|1237||F||42||52||Yes||IgG, C3||Positive||ND||–||–|| |
|1337||NK||63||69||No||IgG, IgM, C3||Neg||ND||–||–|| |
|1437||NK||51||65||No||IgG||1 : 40, 1 : 160 (IC)||ND||–||–||Hypothyroid|
|1537||NK|| ||74||No||Ig G||Positive||ND||–||–||Colon cancer|
|1638||F||7||21||–||IgG, C3/4||BMZ 1 : 80||ND||–||PDN, DDS, AZT|| |
|1739||M||30||31||No||!gG|| ||ND||PDN, AZT||PDN|| |
|1840||M||7||9||Yes||–||Positive||ND||SSZ||PDN, SSZ|| |
Table 3. Summary of case reports of patients with ulcerative colitis (UC) and mucous membrane pemphigoid (MMP) or pemphigoid gestationis (PG).
|142||F||53||MMP||58||Yes||IgG, IgA||IgG BMZ||Negative||PDN, SSZ|| |
|243||F||21||PG||23||NK||IgG, C3||IgG, C3||ND||PDN, DDS||Grave disease, alopecia areata|
Table 4. Summary of case reports of patients with Crohn disease (CD) and autoimmune blistering diseases.
|144||F||LAD||12||13||No||IgA, C3||–||ND||SSZ, BUD||DDS||Anaemia|
|245||F||LAD||55||55|| ||IgA||–||ND||PDN, ASA||DDS, PDN|| |
| ||F||LAD||60||60||Yes||IgA||–||ND|| ||PDN, DDS||Anaemia|
|446||F||LAD||67||68||Yes||IgA*||–||ND|| ||PDN, AZT||Angina|
|547||M||LAD||30||33||No||IgA||–||ND|| ||PDN, DDS||Anaemia|
|749||M||BP||41||43||No||IgG||–||180 kDa||PDN||PE, PDN (IV), CsA||RPGN|
|850||M||BP||10||10||Yes||IgG, C3||IgG||ND||PDN, ASA||AZT|| |
|9†||F||MMP||16||16||Yes||IgG, C3||IgG||180 kDa||PDN, MMF, DDS||PDN, AZT, INF||Angina|
Table 5. Summary of findings from case reports on patients with autoimmune blistering diseases and inflammatory bowel disease (IBD).
|UC + LAD||20||12||8||41|| 8||64||−1 month*||33 years||Four cases: 97, 120, and 210 kDa proteins, BP180|
|UC + BP||19||11||5||45|| 9||83||6 months||23 years||Two cases: BP180, BP230, 200 kDa|
|UC + MMP|| 1|| 0||1||–||58|| ||7 years||–||Neg|
|UC + PG|| 1|| 0||1||–||23|| ||2 years||–||–|
|CD + LAD|| 6|| 1||5||44||13||68||5 weeks||3 years||–|
|CD + BP|| 2|| 2||0||–||10||43||1 years||2 years||BP180 (1 case)|
|CD + MMP|| 1|| 0||1||–||16||–|| ||–||BP180 (1 case)|
Of the 48 patients, 19 had UC plus LAD (Table 1),20–31 and all but one developed UC first and LAD 1–33 years later. The one remaining patient developed LAD 1 month before the UC. The patients were mostly young (median age 41, range 8–64).
The majority of the patients (19) had UC plus BP (Table 2).32–41 Again, all patients except one developed UC before the BP, with a range of 6 months to 23 years between diagnoses. The other patient developed both conditions simultaneously. The median age of the patients was 45 years (range 9–53), which is younger than usual with BP (typically fifth to seventh decades).
The two patients with PG and MMP (23 and 58 years old, respectively) developed UC 2 and 7 years, respectively before they developed their blistering diseases.42,43
There were six patients (median age 44 years; range 13–68) with CD and LAD;44–48 in all cases, the CD developed first, with LAD developing 6 weeks to 3 years later. Two patients had CD and BP; in both cases, the CD developed first, 1 and 2 years, respectively, before the BP appeared.49,50
Features and antibodies
The clinical and immunopathological features and the demographics of all cases are described in Table 5. In all but one case, the IBD diagnosis predated the development of the skin condition. The association was more common for LAD than for BP. One patient with UC and BP had antibodies to BP180, and another had antibodies to BP180, BP230 and a 200 kDa protein. Two patients with CD and UC had antibodies to BP180 (Table 5) thus BP180 was the antigen most commonly associated with IBD in this small series.
We have reviewed the reported cases of an association between the autoimmune blistering diseases and IBD. The association was described most frequently for LAD, even though it is the rarest of these diseases, with 25 cases reported and an incidence of < 0.5 per million per year, although this could reflect reporting bias, compared with 21 cases of BP (incidence of 6–30 cases per million population per year) 2 only MMP cases and 1 PG case (incidences of 1–2 and 0.5 per million per year, respectively).3–6
IBD results in breakdown of the epithelial layer and exposure of the mucosal BM to an immune response. We hypothesize that the association between the two diseases may be related to the exposure of the immune system to autologous antigens in the bowel, which are then recognized in the skin. The demonstration of positive immunofluorescence in the gut in two cases of LAD and CD supports this hypothesis.
IBD is a process driven by T cells,51 particularly CD4 cells. A dysregulation between T-regulatory cells and CD4 cells is hypothesized as the pathogenic mechanism, leading to inflammation and exposure of a large number of ligands to the Toll-like receptors. The driving antigen signal is believed to be flagellin from bacteria; however, release of cytokines, e.g. tumour necrosis factor and interleukins 4 and 17,52 leads to the inflammation and tissue damage, and the presentation of human antigens to inflammatory cells. BP180 is expressed in colon epithelium, and could be presented as an antigen to T cells,53 as could BP230, which is expressed in mouse embryo GI tract.13
All but two of the UC cases reported (Tables 1–3) had the UC present (often years) before the blistering disease developed. There were fewer accounts of the concomitant diagnosis of autoimmune blistering diseases and CD (see Table 4), but the time span between the two diagnoses was much shorter than that for UC, with a range of 5 weeks to 3 years. A summary of the demographics are shown in Table 5.
A Danish study investigating patients with multiple sclerosis (MS) and their first-degree relatives found an association between MS and BP, and also between MS and UC.54 BP antigen is expressed in nerve and muscle tissue,13 and crossreactivity between brain and skin has been proposed as the link.55
Autoimmune diseases may be associated with each other, primarily because of genetic differences in the antigen-handling and inflammation-regulation systems. However, blistering diseases are thought of as antibody-mediated autoimmune diseases, whereas other autoimmune diseases are a combination of T-cell-mediated and antibody-mediated conditions. Recently, however, reactive T cells have been identified in some autoimmune blistering skin diseases,56–58 including BP and MMP.59 The time interval between onset of IBD and blistering would accord with the theory that exposure to antigens in the GI tract eventually leads to skin disease, which is also supported by the positive immunofluorescence staining in the colon in two reported cases46 and the positive immunoblotting for BP180 in four cases.
We report two cases of co-existing blistering disease and IBD. We propose that inflammation in the setting of IBD leads to an immune reaction to the antigen BP180 and induction of BP180-mediated blistering disease. The fact that the association was most frequently found with LAD may be due to the fact that mucosal responses to antigens are often IgA responses, and IgA secretion is also affected in UC.60 There is an interesting parallel in dermatitis herpetiformis, in which intestinal inflammation results in an IgA-mediated blistering condition. Unfortunately, information on which human antigens are under attack in IBD is incomplete, and hence this remains speculation. Future studies may serve to clarify these links and to our understanding both of blistering disease and IBD.
- • Autoimmune subepidermal blistering diseases are antibody-mediated diseases, in which the body mounts an immune response to adhesion proteins in the BM.
- • Associations between BP and neurological disease are well recognized, but associations between autoimmune subepidermal blistering diseases and other diseases are rare, although case reports of the association with inflammatory disease do exist.
- • There seems to be an association with IBD and subepidermal blistering disorders, particularly LAD and BP.
- • The IBD usually predates the skin disease.
What is the approximate incidence of bullous pemphigoid in Europe per year?
a) 0.5 per million of the population
b) 1 per million of the population
c) 5 per million of the population
d) 6–30 per million of the population
e) 50 per million of the population
Antibodies in bullous pemphigoid, pemphigoid gestationis and linear IgA disease normally attack which part of collagen XVII?
c) NC18D domain
d) NC16A domain
e) Triple helical region
Ulcerative colitis is most commonly associated with which bullous disease?
a) Bullous pemphigoid
b) Mucous membrane pemphigoid
c) Linear IgA disease
e) Pemphigoid gestationis
What is the age range of patients with bullous pemphigoid and inflammatory bowel disease?
a) 8–64 years
b) 9–83 years
c) 13–68 years
d) 10–43 years
e) 16–68 years
What is the usual time relationship between the appearance of inflammatory bowel disease and linear Ig A disease?
b) Blisters precede the inflammatory bowel disease
c) Inflammatory bowel disease precedes the blisters
d) No pattern
Inflammatory bowel disease is driven by which cell type?
a) CD4 cells
b) CD8 cells
c) T-regulatory cells
d) B cells
e) Mast cells
Collagen XVII (BP180) is important in which part of the epidermis?
a) Collagen XVII tight junction
d) Gap junction
e) Leaky junction
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