Ulcerative colitis and bullous pemphigoid: Direct association or a medication side effect: A case report

Abstract

BACKGROUND

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. It is associated with other autoimmune disorders and the use of certain drugs. We describe a case of BP in a patient with ulcerative colitis (UC) treated with mesalamine.

CASE SUMMARY

A 38-year-old male patient with UC and a history of multiple flares was maintained on mesalamine with good clinical response. One year after starting mesalamine, he sought medical care following the onset of a severe itchy rash of several weeks’ duration with a recent appearance of skin bullae. A biopsy of the skin revealed subepidermal blistering dermatitis with focal eosinophilic spongiosis. Direct immunofluorescence studies revealed linear IgG and C3 immune reactant deposits at the dermoepidermal junction, consistent with the diagnosis of BP. Prednisone therapy alleviated his symptoms. However, tapering prednisone led to re-eruption of the bullae.

CONCLUSION

BP should be considered when patients with UC develop skin manifestations. Although BP is not one of the extraintestinal manifestations of UC, there may be an association between these two conditions. Whether treatment with mesalamine or other therapeutic agents plays a role in the development of BP remains unclear.

Key Words: Bullous pemphigoid; Ulcerative colitis; Autoimmune disorders; Skin manifestations in inflammatory bowel diseases; Mesalamine; Case report

Core Tip: Physicians should be aware of the possibility that bullous pemphigoid (BP) could develop in patients with ulcerative colitis (UC). Although it is not listed as a known extraintestinal manifestation in UC, BP should be kept on the differential diagnosis list when patients with UC develop a skin condition. Whether BP is associated with UC or its treatment remains unclear. The fact that different agents have been incriminated in several reports makes the possibility of an association with the disease itself, rather than its treatment, more plausible.

INTRODUCTION

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the formation of subepidermal blisters. These characteristic skin lesions result from IgG1 and IgG4 autoantibodies against hemidesmosomes, specifically the BP180 and BP230 antigens[1]. BP has a predilection for the older population. In the USA, studies have shown a rise in BP incidence with age, from 2.4-23 cases per million in the general population to 190–312 cases per million upon reaching the seventh decade of life[2]. This is specifically true in patients with autoimmune disorders, such as Hashimoto’s thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, or those taking certain medications. Drug-induced BP is associated with the use of sulfa drugs, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, dipeptidyl peptidase-IV inhibitors, and tumor necrosis factor-alpha (TNF)-α inhibitors[2]. While BP is not considered one of the extraintestinal manifestations of inflammatory bowel disease (IBD), there have been reports of its occurrence in patients with ulcerative colitis (UC), some of whom were taking mesalamine. We describe a case of a patient with UC who developed BP while taking mesalamine.

CASE PRESENTATION

Chief complaints

Diffuse blistering skin eruption.

History of present illness

We report a case of a 38-year-old male patient, known to have UC, in clinical remission on 4 g/d mesalamine. His disease was confined to the rectum on initial presentation, and he was treated with mesalamine suppositories for 3 mo with good clinical response. He had multiple mild flares treated with both rectal and oral mesalamine but never pursued a repeat colonoscopy although recommended by his physicians. During these mild flares, he took mesalamine only for short periods despite clear recommendations regarding the need to stay on the treatment long term. Three years after the initial presentation, he presented again with diarrhea and hematochezia in addition to abdominal pain and elevation in C-reactive protein and stool calprotectin. A colonoscopy showed pancolitis with moderate severity (endoscopic Mayo score 2). He was started on a tapering course of steroids and maintained on mesalamine with a plan to start vedolizumab. He remained in clinical remission with normal inflammatory markers and declined starting any additional therapeutic agents as he was feeling well. One year after starting mesalamine and taking it without interruption, he presented following the onset of a severe itchy rash with a recent appearance of skin bullae. At the time of this presentation, he had mild gastrointestinal symptoms consisting of mild left sided abdominal pain, one to two loose bowel movements per day and occasional rectal bleeding. On physical examination, numerous annular erythematous lesions and scattered tense bullae on the extremities and the abdomen were noted (Figure 1).

Figure 1  Diffuse eruption of annular erythematous lesions and scattered tense blisters throughout the body.

A colonoscopy was ordered to assess disease activity but was never completed as the patient preferred to pursue further work-up and treatment of his rash. A skin biopsy revealed subepidermal blistering dermatitis with focal eosinophilic spongiosis. Direct immunofluorescence studies revealed linear IgG and C3 immune reactant deposits at the dermoepidermal junction, consistent with the diagnosis of BP. The patient was started on a course of 20 mg of prednisone, which alleviated his blistering eruption. Prednisone was then tapered to 10 mg once daily, which resulted in the reappearance of the rash. A course of 20 mg prednisone was then re-implemented, resulting in total subsidence of the rash.

The patient was referred to a dermatologist for further treatment of his condition and was advised again to pursue a colonoscopy. Unfortunately, he was subsequently lost to follow-up.

History of past illness

UC.

Physical examination

On physical examination, numerous annular erythematous lesions and scattered tense bullae on the extremities and the abdomen were noted.

Laboratory examinations

Within normal limits.

FINAL DIAGNOSIS

BP.

TREATMENT

The patient was started on a course of 20 mg prednisone, which alleviated his blistering eruption. Prednisone was then tapered to 10 mg once daily, which resulted in the reappearance of the rash. A course of 20 mg prednisone was then re-implemented resulting in total subsidence of the rash.

OUTCOME AND FOLLOW-UP

The patient was referred to a dermatologist for further treatment of his condition and was advised again to pursue a colonoscopy. Unfortunately, he was subsequently lost to follow-up.

DISCUSSION

UC is a chronic IBD characterized by mucosal inflammation, starting from the rectum with a potential of spreading throughout the colon without skipped lesions. Symptoms of UC include bloody diarrhea, abdominal pain, and tenesmus[3].

UC is often associated with extraintestinal manifestations[3]. Cutaneous manifestations of UC can be classified in several subgroups based on their histological features or their immunological patterns. These manifestations include erythema nodosum, pyoderma gangrenosum and in less frequent cases, Sweet syndrome[4]. Psoriasis and vitiligo are other skin conditions that can be associated with UC[4]. BP is not typically considered as a skin manifestation of UC.

Treatment of UC, including mesalamine, immunomodulators and corticosteroids, can vary depending on the severity of the inflammation, extent of the disease, and the patient’s comorbidities[5].

Many case reports have documented the potential association between specific drugs used in UC patients and the development of BP. In our case, the patient was doing well on a regimen of 4 g mesalamine once daily with no significant flares of UC. One year later, he developed mild gastrointestinal symptoms and a blistering skin eruption diagnosed as BP on histopathology. Mesalamine was not discontinued. A course of corticosteroids, consisting of 20 mg prednisone, relieved the patient’s rash.

Two case reports by Fujimoto et al[6] and Siegel et al[7] reported the development of BP in patients with UC and taking mesalamine[6,7]. In the case of the 12-year-old male treated with mesalamine and prednisolone, BP erupted upon tapering the prednisolone dose from 30 mg to 5 mg daily[6]. In another case, 2 wk after starting mesalamine (with no previous steroid use), an 85-year-old male suddenly developed a blistering skin rash, later confirmed to be BP, and was subsequently treated with 40 mg prednisolone for 2 wk[7].

According to other case reports in the literature, similar skin complications were also seen in UC patients receiving TNF-α inhibitors as a first-line treatment. Hoffman et al[1] and Wessman et al[8] report BP occurrences in male patients a few days after the second injection of the second cycle of adalimumab and 1.5 years after starting adalimumab, respectively[1,8].

A similar presentation was seen in two patients receiving infliximab for UC. Li et al[9] describe a case of a 51-year-old male patient found to have BP after the fifth cycle of infliximab[9]. Similarly, Tani et al[10] reported a case of a 69-year-old female who developed BP 3 wk following her third dose of infliximab[10]. In all these cases, corticosteroid therapy successfully relieved BP. One plausible explanation is the increase of autoantibodies in patients on TNF-α inhibitors[11]. However, a causative correlation cannot be proven. In all these cases, it is unclear if the association is between BP and the therapeutic agent or with UC itself.

Selby et al[12] reported two cases of BP in patients with UC treated with mesalamine. The authors suggest two hypotheses regarding the eruption of BP. The first posits an immune dysregulation process as both UC and BP are mediated by a Th2 immune response and are associated with other autoimmune diseases, such as Hashimoto’s thyroiditis[12]. The second hypothesis endorses a mesalamine-induced BP as was illustrated in a case report where the patient had positive patch skin testing to sulfasalazine and his BP subsided after mesalamine withdrawal[13]. Several studies have identified a protein called plectin, which shares similarities with BP230, and is present in the skin and bowel[12]. Increased colonic permeability and the release of colonic antigens that may crossreact with skin antigens have been proposed to explain the link between BP and UC[14-16]. In one case, colectomy was associated with a cure of immunobullous skin diseases in the context of UC further highlighting that an inflamed colon is the inciting agent for the development of BP[17].

A large population-based case–control study by Chen et al[18] of 5263 BP patients failed to establish an association between BP and IBD treatment. UC was found to be significantly associated with BP, with an adjusted odds ratio of 3.60 (95% confidence interval 1.91–6.77, P < 0.001)[18]. In contrast, there was no significant association between UC treatment and BP. This may have been affected by the small number of patients with UC in that study as well as the paucity of data concerning the history of the disease and the treatment protocol in each patient[18].

The average age of onset for BP typically falls between 60 and 80 years[19]. However, in many cases documenting the occurrence of BP in patients with UC, BP manifested before the fifth decade[12]. This early onset suggests the possibility that UC itself could be contributing to an earlier presentation of this autoimmune skin condition.

In summary, based on the current body of literature, it is difficult to ascertain whether BP is associated with UC or its treatment. As mentioned previously, different reports looking at the association between BP and UC incriminated several therapeutic agents. Given the different mechanism of action of these therapeutic agents, it is less plausible that BP developed due to the treatment itself. In our patient's case, the lack of follow-up and the inability to assess UC activity when BP occurred are limitations that hinder drawing any conclusions about the relationship between BP and UC or its treatment.

CONCLUSION

Physicians should be aware of the possibility that BP could develop in patients with UC. Although it is not listed as a known extraintestinal manifestation in UC, BP should be kept on the differential diagnosis list when treating patients with UC who develop a skin condition. It is unclear if BP is associated with UC or its treatment. The fact that different agents have been incriminated in several reports makes the possibility of an association with the disease itself, rather than its treatment, more plausible.