A case of bullous pemphigoid in an ulcerative colitis patient treated with vedolizumab

Introduction

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease with onset typically after the age of sixty caused by autoantibodies against the hemidesmosomal components BP antigen 180, also known as BPAG2 or type XVII collagen, and BP antigen 230, also known as BPAG1e. Disease presentation is variable ranging from pruritus with eczematous to urticarial lesions to wide-spread tense vesicles and bullae. Diagnosis is established with skin biopsy for hematoxylin and eosin and direct immunofluorescence, indirect immunofluorescence, and/or enzyme-linked immunosorbent assay for anti-BP180 and BP230 autoantibodies. Though rare, associations with inflammatory bowel disease (IBD) and other autoimmune disorders have been described with ulcerative colitis (UC) as the most commonly cited IBD.¹ Several medications have been implicated in the onset of BP, namely gliptins, programmed cell death protein-1 and ligand-1 inhibitors, loop diuretics, penicillins, nonsteroidal anti-inflammatory drugs, and thiazides among others.²

Vedolizumab, a monoclonal antibody against α4β7 integrin, was approved in 2014 for the treatment of both moderate-to-severe UC and Crohn’s disease. Due to its gut-selectivity and favorable safety profile compared to other systemic immunosuppressants this treatment option is gaining favor for the management of IBDs.³ As with any emerging treatment, careful monitoring and consideration of its role in the development of previously undocumented side effects is vital. Accordingly, we present a case of BP in a patient with UC treated with vedolizumab. While the precise role of vedolizumab in the development of this patient’s autoimmune bullous disorder remains uncertain, we propose theories for this potential link and stress the importance of dermatologic surveillance and reporting of side effects in patients receiving integrin-targeting therapies.

Case presentation

We present a case of a 47-year-old man with 6-year history of UC who presented with a 3-week history of rash which began as an urticarial papule to his right leg and progressed to a pruritic urticarial and vesiculobullous eruption involving his trunk and all extremities without involvement of mucosal surfaces (Fig 1). Notable medication changes include vedolizumab infusions started 14 weeks prior for UC uncontrolled on mesalamine and budesonide.

Fig 1.

Clinical presentation. Admission with urticarial, erythematous edematous plaques (A and B) with scattered overlying tense bullae (B and C). Hospital day 6 with progression of vesiculobullous disease (D and E).

Physical examination revealed erythematous, edematous papules and plaques to the trunk and extremities with overlying vesicles and bullae and scattered serum and heme-crusted papules. A biopsy for hematoxylin and eosin and direct immunofluorescence showed a subepidermal blister with mixed inflammatory infiltrate predominated by eosinophils with direct immunofluorescence positivity for C3 and IgG deposition at the dermal-epidermal junction consistent with a diagnosis of BP (Fig 2). Enzyme-linked immunosorbent assay was positive for antibodies against BP180 antigen (183 U/mL, positive >9 U/mL).

Fig 2.

Histopathology. Hematoxylin and eosin (H&E) at 200× original magnification (A) and 400× original magnification (B) demonstrating subepidermal blister with mixed inflammatory infiltrate predominated by eosinophils. Direct immunofluorescence (DIF) with C3 (C) and IgG (D) deposition along the dermal-epidermal junction.

Given the diffuse and progressive nature of his vesiculobullous disease he was initiated on (1) topical corticosteroids (clobetasol 0.05% ointment), (2) systemic corticosteroids (his home budesonide was transitioned to prednisone 60 mg twice a day with subsequent taper), (3) rituximab (two 1 g infusions separated by 2 weeks), (4) azathioprine (100 mg daily later increased to 200 mg daily), and (5) doxycycline (100 mg twice a day for both BP and concerns for impetigo). This multifactorial approach has improved, but not fully cleared his BP; therefore, dupilumab was ultimately initiated.

For the management of his UC, vedolizumab infusions were discontinued due to concern for drug-induced BP, oral mesalamine was transitioned to suppositories, azathioprine was initiated as above, and initiation of infliximab is being considered.

Discussion

This case highlights the significant complication of BP in a patient with UC undergoing treatment with vedolizumab. Vedolizumab, as a relatively new treatment option, has the potential for inducing side effects previously unknown. While the mechanism of vedolizumab is primarily gut-specific, we propose that this biologic therapy may contribute to immune dysregulation beyond the gastrointestinal tract and contribute to the development of BP through mechanisms involving epitope spreading, altered lymphocyte trafficking, and immune homeostasis disruption.

First, as previously stated, UC is the most commonly cited IBD associated with the development of BP.¹ The chronic inflammatory state in IBD may expose neoantigens to immunodetection leading to an epitope spreading phenomenon.⁴ As its name implies, UC results in ulceration of the intestinal lining which may result in greater exposure of these neoantigens than the granulomatous inflammation seen in Crohn's. This may explain the higher rates of BP seen in UC compared to Crohn’s.

With this baseline susceptibility, the addition of vedolizumab may contribute by disrupting the gut-skin immune axis. Through the blockage of α4β7 integrin, vedolizumab prevents migration of gut-homing effector T-cells into intestinal tissues.⁵ This likely results in redistribution of lymphocytes to non-gut compartments including the skin where they may contribute to autoimmune dysregulation. These redistributed α4β7+ lymphocytes may recognize structurally similar epitopes in the dermal-epidermal junction and trigger cross-reactive autoimmunity. Importantly, BP180 is expressed in normal colonic epithelium.⁶ The shared antigenic target (BP180) in both the gut and skin suggests that autoantibody production could be initiated in the GI tract and later manifest as cutaneous BP. Interestingly, unlike BP180, BP230 is primarily expressed in neurons, muscle and stratified squamous epithelium; thus, it is not surprising that our patient was positive only for BP180 antibodies.⁷

Furthermore, other biologic agents such as tumor necrosis factor-α inhibitors and programmed cell death protein-1 inhibitors have been implicated in the development of BP, suggesting that immune modulation therapies may inadvertently unmask immunobullous diseases.² Furthermore, biologics used for the treatment of IBD specifically have been associated with other autoimmune phenomena, including psoriasis, drug-induced lupus, and other paradoxical skin eruptions with vedolizumab specifically implicated in the development of drug-induced lupus⁸ and psoriasis.⁹

Conclusion

This case of BP in a UC patient treated with vedolizumab presents a potential link between this biologic and the paradoxical development of another autoimmune condition and underscores the importance of dermatologic surveillance in IBD patients receiving integrin-targeting therapies.

Conflicts of interest

None disclosed.