Ulcerative colitis complicated with linear immunoglobulin A bullous dermatosis

Abstract

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disorder involving subepidermal blistering characterised by IgA deposition along the basement membrane. The clinical features of LABD are variable but can include bullae, vesicles and erythematous lesions. Histopathology reveals formation of subepidermal bullae and linearly deposition of IgA in the basement membrane of the epidermis. LABD has been reported as a rare complication of ulcerative colitis (UC). We report the case of a young woman with UC complicated by LABD. The latter manifested as vesicles with erythema on almost the entire body. A biopsy of the skin lesions revealed linear IgA deposits in the basement membrane according to a direct immunofluorescence assay. Prednisolone administration resulted in clinical remission of UC but poor improvement of skin lesions. Oral administration of diaminodiphenyl sulfone led to improvement of blisters. Thereafter, abdominal and skin symptoms did not recur and she was discharged from hospital.

Background

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that causes symptoms such as haematochezia, diarrhoea and abdominal pain. The mechanisms involved in UC development are incompletely understood and the aetiology is not known. Factors such as heredity, intestinal bacteria and the environment have been suggested to be the cause of UC.^{1 2} The latter elicits extraintestinal complications such as joint pain/arthritis, skin lesions, thrombosis and primary sclerosing cholangitis. Of these, skin lesions are associated with ~15% of patients with inflammatory bowel disease.³ Erythema nodosum, pyoderma gangrenosum and Sweet syndrome are major skin diseases associated with UC. In addition, the prevalence of skin lesions as complications associated with therapeutic agents taken to counteract UC (eg, the psoriasis-like rash that occurs during administration of antitumour necrosis factor-α preparations) has been increasing in recent years.

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is an autoimmune blister. It is characterised by immunohistology as linear deposition of IgA in the basement membrane and presents as a subepidermal blister.^4–11 LABD is associated with drug use and malignant tumours, but rare cases of LABD as a complication of UC have been reported.^5–13 Here, we report LABD associated with UC.

Case presentation

The patient was a woman in her 20s with no family/medical history of disease. She visited a hospital complaining of diarrhoea of several-month duration. She underwent colonoscopy and was diagnosed with pancolitis. UC treatment was started with 5-aminosalicylic acid (mesalazine; 3600 mg) which led to clinical remission, but UC relapse occurred 7 months later. Oral administration of prednisolone (PSL) 30 mg p.o. was started and symptoms improved. PSL was tapered off over 3 weeks, but the patient relapsed after discontinuation of PSL. At approximately the same time, she noticed itchy blisters on her right thigh. The skin lesions spread gradually throughout her body, and she subsequently developed a high fever, so she visited our hospital.

On consultation, consciousness was clear, blood pressure was 110/50 mm Hg, pulse was 72 /min, respiratory rate was 18 /min and body temperature was 38.2°C. She had mild tenderness in the lower abdomen. Pruritic erythematous plaques and overlying vesicles and bullae were present on almost the entire body except her face.

Investigations

Tight blisters and pustules were observed in some skin lesions (figure 1). Blood tests showed a potent inflammatory response and hypoalbuminemia. CT scan of the abdomen showed extensive oedematous thickening of the intestinal wall in the colon (figure 2). Colonoscopy revealed inflammation of the entire colon (figure 3). The Lichtiger Index (which indicates the clinical activity of UC) was 11 points. She was diagnosed with UC of moderate activity.

Figure 1.

Skin lesions on hospital admission. (A) Erythema, blisters, erosions and pigmentation are mixed. (B) Blisters are found on erythema.

Figure 2.

Contrast-enhanced CT scan of the abdomen on hospital admission. The wall of the (A) ascending colon, descending colon and (B) sigmoid colon is thickened. The lesions are shown with arrows.

Figure 3.

Colonoscopy on hospital admission (white-light imaging; Olympus PCF-H290I). (A) Ascending colon, (B) descending colon, (C) sigmoid colon and (D) rectum show an absent vascular pattern, friability and marked erythema.

Histology of a skin biopsy showed subepidermal bullae (figure 4). Direct immunofluorescence revealed linear deposits of IgA in the basement membrane of the epidermis (figure 5). A diagnosis of LABD was made based on these findings.

Figure 4.

Subepidermal blister. (A) A subepidermal blister contains fibrinous inflammatory exudate. (B) Many eosinophils and neutrophils are present in the subepidermal blister. Epidermal necrosis is minimal. H&E stain, original magnification for (A) is ×200 and for (B) is ×400.

Figure 5.

Direct immunofluorescence of perilesional skin. A linear pattern of immunoglobulin A deposition at the dermal–epidermal junction is seen.

Treatment

On the eighth day of hospitalisation, PSL (50 mg) infusion was started with the expectation of efficacy against UC and LABD. Gastrointestinal symptoms improved from 1 day after PSL administration, and the Lichtiger Index improved (from 11 points to 2 points) 3 days after starting PSL.

PSL 50 mg was continued, but because improvement of skin lesions was poor, diaminodiphenyl sulfone (DDS (rectisol), 50 mg p.o.) was started on day 21 of hospitalisation.

Outcome and follow-up

On DDS administration, the lesions caused by LABD improved (figure 6). DDS was successful and no side effects were observed, and the dose was increased to 75 mg p.o. on the 24th day of hospitalisation. The dose of PSL was reduced to 40 mg intravenously on the 27th day of hospitalisation and then switched to the same dose of oral medication 3 days later, with no relapse of abdominal or skin symptoms. As the abdominal and skin symptoms were in clinical remission, the PSL dose was tapered gradually and DDS was continued at the same dose. She was discharged from hospital on day 32.

Figure 6.

Skin findings on day 14 of diaminodiphenyl sulfone administration. (A) Erythema is present but is starting to fade. (B) The blisters have improved.

Discussion

LABD is characterised by the formation of clinically tense bullae and vesicles arranged in an annular pattern on an erythematous surface. The differential diseases of LABD include bullous pemphigoid, erythema multiforme, dermatitis herpetiformis and toxic epidermal necrolysis.^4–6 Histopathological and direct immunofluorescence findings are necessary for differential diagnosis.

Histopathology shows subepidermal bullae formation and IgA to be deposited linearly in the basement membrane of the epidermis. The triggers for LABD are not known, but drugs^5–9 or an association with malignancy^10–13 have been suggested. LABD as a complication of UC has also been reported.^{14 15}

Several hypotheses have been postulated for the relationship between UC and LABD. Yamada et al¹⁶ speculated that the intestinal mucosal damage caused by UC induces an excessive immune response to foreign antigens and autoantigens. This action leads to the production of anti-IgA antibodies against the causative antigens of bullous skin disease, such as BP180 and collagen type VII, which results in LABD development. Wojnarowska et al showed that in patients with LABD, the serum level of IgA1 was increased and a direct fluorescent antibody assay showed IgA1 deposition in the basement membrane of skin.¹⁷ Thiago et al reported that the intestinal mucosa of patients with UC secretes a high ratio of IgA1:total IgA and that UC and LABD are related.¹⁸

Several scholars have focused on the correlation between the disease activity of UC and LABD. Some researchers have reported that LABD remains active after colectomy and that LABD activity is not associated with UC activity.^{14 19} Other scholars have reported sustained complete remission of LABD after colectomy.^{18 20 21} One case study reported that LABD showed no activity if the UC Activity Index<180 and recurred if it was >190.¹⁵ Also, in many cases of UC complicated with LABD, UC precedes LABD (median, 6.5 years), suggesting that the chronic intestinal inflammation observed in UC may be a cause of LABD development.^{16 17} In our patient, UC preceded LABD onset, and LABD developed at the time of UC relapse. Although many kinds of drug can induce LABD, there are no reports showing the causal relationship between 5-aminosalicylic acid and LABD.⁵ Only a case of LABD caused by sulfasalazine, an azo compound 5-aminosalicylic acid with sulfapyridine, was reported.⁷

Clear guidelines have not been established for treatment of UC complicated with LABD. Reported cases of UC complicated with LABD are shown in table 1.15 16 18 20–33 Since 2000, 18 cases have been reported. In many cases, basic therapeutic agents such as 5-aminosalicylic acid were administered for UC and, in some cases, PSL was administered in consideration of its efficacy against LABD and UC. As in our case, DDS has been administered to counteract LABD. In general, administration of DDS or topical/systemic corticosteroids is employed frequently against LABD. DDS suppresses cytokine production from immune cells, as well as inhibiting production of Ig molecules and active oxygen molecules. Therefore, DDS is considered first-line therapy against LABD. The efficacy of infliximab (IFX) and other biologic agents against LABD is controversial. Yamada et al reported that IFX introduction improved UC and LABD.¹⁶ Conversely, some scholars have reported that IFX was not efficacious against LABD.^{23 24}

Table 1.

Reported cases of UC complicated with LABD

No.	Author/references	Year	Age at diagnosis (years)		Gender	Treatment
			UC	LABD		Pre LABD	Post LABD
1	Our case	2021	19	20	F	ASA	PSL, DDS
2	Kanda et al25	2020	57	59	F	ASA	ASA, PSL, DDS
3	Sonoyama et al22	2020	15	18	M	ASA	ASA, PSL, AZA
4	Onoe et al26	2017	23	23	M	–	ASA
5	Bryant et al24	2016	50	54	M	IFX	PSL, ADA
6	Sotiriou et al21	2015	45	49	M	PSL	PSL, DDS
7	Sotiriou et al21	2015	38	44	F	–	ASA, DDS
8	Hoffmann et al23	2015	35	49	M	ASA, AZA, IFX	ASA, PSL, DDS
9	Kern et al27	2014	47	48	M	ASA	PSL, AZA, DDS, IFX
10	Watchorn et al20	2013	43	46	F	AZA	PSL, DDS, colectomy
11	Vargas et al18	2013	12	13	M	ASA, PSL, ADA	PSL, DDS, colectomy
12	Yamada et al16	2013	19	34	F	PSL, SSZ	DDS, IFX
13	Sandoval et al28	2012	18	18	F	–	PSL, flucloxacillin
14	Shipman et al29	2012	38	40	M	PSL, SSZ	DDS
15	Klein et al30	2010	36	48	M	PSL, AZA	PSL, DDS
16	Caldarola et al31	2009	23	24	M	–	ASA, AZA, DDS, colectomy
17	Taniguchi et al15	2008	27	28	F	ASA, PSL	–
18	Keller et al32	2003	54	54	M	–	ASA, PSL, DDS
19	Walker et al33	2000	30	43	F	PSL, AZA	PSL

ADA, adalimumab; ASA, aminosalicylic acid; AZA, azathioprine; DDS, diaminodiphenyl sulfone; F, female; IFX, infliximab; LABD, linear IgA bullous dermatosis; M, male; PSL, prednisolone; SSZ, sulfasalazine; UC, ulcerative colitis.

We diagnosed a patient with LABD associated with UC. We treated her with PSL and DDS. If skin lesions such as widespread erythema and blistering appear in patients with UC, although it is rare, LABD should be taken into consideration.

Learning points.

• Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare, subepidermal blistering disease characterised by deposition of IgA along the basement membrane.

• Skin lesions are an extraintestinal complication of ulcerative colitis (UC), but LABD is rare.

• Diaminodiphenyl sulfone and topical/systemic corticosteroids are employed frequently for LABD, but clear guidelines for treatment of UC complicated by LABD have not been established.

• If skin lesions such as widespread erythema and blistering appear in patients with UC, the complication of LABD should be considered.

• Many cases of LABD are preceded by UC, and whether their activity is correlated is not known.

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