Resolution of Laryngeal Ulceration with Prednisolone Therapy in a Patient with Crohn's Disease

Abstract

A 23-year-old man diagnosed with Crohn's disease (CD) was treated with infliximab. He developed new-onset sore throat and dysphagia during admission, and nasopharyngoscopy revealed epiglottic ulceration. Laryngeal ulceration was considered as an extraintestinal manifestation of CD owing to treatment failure with antibiotics and hydrocortisone. This strongly suggested that laryngeal ulceration was a complication of CD because of the rapid improvement in the symptoms and lesions after prednisolone administration. Furthermore, this treatment process demonstrated the superior anti-inflammatory effect of prednisolone over that of hydrocortisone and supported the assumption of inflammation related to CD.

Introduction

Crohn's disease (CD) is a chronic autoimmune inflammatory disease that can cause granulomatous inflammatory lesions in any portion of the gastrointestinal (GI) tract, from the oral cavity to the anus (1,2). Involvement of the distal small bowel and variable segments of the colon is typical. However, involvement of organs other than those in the GI tract, such as the skin, eyes, joints, and endocrine system, can also occur as a phenomenon known as extraintestinal manifestation of CD (2,3).

As extraintestinal manifestations of CD, oral ulceration and edema are commonly seen in the head and neck, whereas laryngeal involvement is rare and has been reported in only a few cases (3). Swelling and ulceration of the supraglottic area, including the epiglottis and arytenoids, can cause voice changes, painful swallowing, and dysphagia (1).

We herein report a case of CD with laryngeal ulceration that was resolved by prednisolone therapy.

Case Report

A 23-year-old man with suspected inflammatory bowel disease (IBD) on colonoscopy was referred to our department. His medical history included acute myeloid leukemia at one year old, with remission achieved with chemoradiotherapy and umbilical cord blood transplantation, although a short stature was noted as a treatment side effect.

A tendency toward diarrhea was noted from his teenage years, and watery diarrhea persisted for a year. Initially, he was under conservative treatment for irritable bowel disease at a local clinic; however, the symptoms were not relieved. He also had recurrent oral ulcerations five months prior to referral to our hospital. Red skin patches over the limbs with silvery scales were noted 2 months ago, and psoriasis vulgaris was diagnosed and treated with topical agents at a dermatology clinic. The frequency of watery diarrhea increased to eight times per day a month ago, and anal pain simultaneously appeared. Postprandial abdominal pain was noted a week ago, and the frequency of watery diarrhea progressed to 15 times per day.

IBD was suspected on colonoscopy, and 5-aminosalicylic acid (Pentasa^Ⓡ, 3,000 mg/day) was prescribed at a local clinic 3 days before referral to our hospital. However, the symptoms persisted, and the patient was soon admitted to our hospital for a further evaluation and management.

Colonoscopy showed non-contiguous irregular or round ulcerations from the ascending to the descending colon, while normal mucosa was recognized in between. Deep ulcerations were observed in the transverse and descending colons, part of which were in a longitudinal arrangement (Fig. 1). Active and chronic inflammatory infiltrates were observed in the biopsy specimen, and a noncaseating epithelioid cell granuloma was identified in the ascending colon. Based on these findings, a definite diagnosis of CD was made in accordance with the Japanese diagnostic criteria for CD. Multiple erosions were observed in the gastric corpus and duodenal bulb on esophagogastroduodenoscopy, both of which had chronic inflammatory infiltrates on a biopsy examination without any granuloma formation. No specific lesions were identified on small bowel flow-through, leading to the diagnosis of colitis-type CD (classified as L2 in the Montreal classification).

Figure 1.

Non-contiguous irregular ulcerations from the ascending to the descending colon are noted on colonoscopy, with focal areas of normal mucosa in between. Deep ulcerations in a longitudinal arrangement are seen at the transverse and descending colons, leading to the diagnosis of Crohn’s disease (a: terminal ileum, b: cecum, c: ascending colon, d: transverse colon, e: descending colon, f: anal area).

A perianal abscess was identified on contrast-enhanced computed tomography, and surgical drainage was performed on the 7th day after admission. Since the diagnosis of moderately active CD [Crohn's disease activity index (CDAI) of 291] with several risk factors, such as severe colonic and anal lesions, was confirmed, infliximab (IFX) 5 mg/kg was started the next day (day 8 of admission).

The patient complained of a sore throat after the surgery for the anal lesion, which was initially considered the symptom after tracheal intubation for general anesthesia. Mild swelling of the right tonsil and pharyngeal erythema were noted. A rapid test for group A streptococcal infection yielded positive findings, and oral amoxicillin 500 mg every 12 hours was prescribed. However, his sore throat continued to progress, leading to severe dysphagia.

An otolaryngologist was consulted, and nasopharyngoscopy revealed an ulceration on the right side of the epiglottis. Generally, the differential diagnosis of epiglottic ulcerations include bacterial and viral infections. Furthermore, when oropharyngeal ulceration is noted simultaneously with IBD, other infectious diseases, such as tuberculosis and syphilis; inflammatory/infiltrative diseases, such as Behçet's disease; sarcoidosis; and malignancies, such as lymphoma, should also be ruled out. An interferon-gamma releasing assay for tuberculosis and rapid plasma regain (RPR) and Treponema pallidum latex agglutination (TPLA) tests for syphilis were all negative. Behçet's disease and sarcoidosis were excluded by the absence of typical symptoms and findings according to the diagnostic criteria. Lymphoma and other neoplasms were also unlikely since no malignancy was identified on colon biopsies, and blood tests showed tumor markers within normal ranges (Table). Viral infection with cytomegalovirus, Epstein-Barr virus, or Herpes simplex virus was ruled out by a serological examination.

Table.

Laboratory Data during Admission.

Blood tests	Results
PRP	Negative
TPLA	Negative
T-Spot	Negative
ANA	<40	dil
Anti-dsDNA	<10	IU/mL
PR3-ANCA	1.2	U/mL
MPO-ANCA	<1.0	U/mL
CA19-9	6	U/mL
CEA	<1.8	ng/mL
sIL-2R	462	U/mL
C7-HRP	Negative
EBVCA IgG	80	dil
EBVCA IgM	<10	dil
Anti-EBNA	<10	dil
HSV IgG	<2.0	dil
HSV IgM	0.24	dil
VZV IgG	36.5	dil
VZV IgM	0.37	dil

RPR: rapid plasma regain, TPLA: treponema pallidum latex agglutination, T-Spot: tuberclosis specific interferon-gamma releasing assay, ANA: antinuclear antibody, Anti-dsDNA: anti-double stranded DNA, PR3-ANCA: anti-proteinase 3 antineutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, CA19-9: cancer antigen 19-9, CEA: carcinoembryonic antigen, sIL-2R: soluble interleukin-2 receptor, C7-HRP: cytomegalovirus pp65 antigen, EBVCA: Epstein-Barr virus capsid antigen: Anti-EBNA: anti-EBV nuclear antigen, HSV: herpes simplex virus, VZA: Varicella-Zoster virus

Since group A streptococcal infection was noted, the antibiotics were switched to ampicillin/sulbactam 3 g every 12 hours for another week. In addition, steroid therapy with intravenous hydrocortisone for pharyngeal edema was administered simultaneously for 3 days (200 mg for the first day and 100 mg for the following 2 days). However, the sore throat was not relieved, and the epiglottic ulceration worsened, as noted on nasopharyngoscopy (Fig. 2). Therefore, laryngeal ulceration was considered an extraintestinal manifestation of CD. Intravenous prednisolone (30 mg/day) was started on day 25 of admission, and the symptoms improved immediately within 1 week. Nasopharyngoscopy also showed remarkable improvements in the epiglottic ulcerations (Fig. 3). Prednisolone was then orally administered and decreased to 20 mg/day for administration for another week. At the time of discharge, prednisolone 10 mg/day was being administered and gradually tapered off within 2 weeks without any relapse of laryngeal ulceration.

Figure 2.

Despite treatment with antibiotics and hydrocortisone, the symptoms of sore throat and dysphagia persisted. Nasopharyngoscopy shows worsening of the epiglottic ulcerations (a: first nasopharyngoscopy on day 19, b: follow-up on day 21 of admission).

Figure 3.

Since sore throat and dysphagia persisted, intravenous prednisolone was started on day 25 of admission, and the symptoms improved immediately within 1 week. Nasopharyngoscopy performed approximately 1 and 2 weeks after prednisolone administration shows remarkable improvement in the epiglottic ulcerations. (a: day 33 of admission, b: day 40 of admission)

Regarding the abdominal symptoms, the abdominal pain resolved, and the serum C-reactive protein level improved remarkably after the first infusion of IFX on day 8 (CDAI before and after the first infusion: 291 and 260, respectively; C-reactive protein (CRP) before and after the first infusion: 13.8 and 1.9 mg/dL, respectively). Diarrhea was relieved from 8 to 3 times per day after the second infusion of IFX on day 22 (CDAI before and after the second infusion: 260 and 192, respectively).

The patient was discharged on day 45, and IFX was administered every 8 weeks at the outpatient department. IFX (5 mg/kg every other week) was continued with 5-aminosalicylic acid (Pentasa^Ⓡ, 3,000 mg/day) and elemental diet agent (Elental^Ⓡ; 160 g/day; EA Pharma, Tokyo, Japan), without immunomodulatory agents. No recurrence of laryngeal ulceration was noted, and the resolution of the CD activity was confirmed on follow-up colonoscopy one year after the diagnosis.

Ethics

Informed consent for publication was obtained from the patient. This study was conducted in accordance with the Declaration of Helsinki, and no ethical committee approval was required owing to the study type.

Discussion

We herein report a case of CD presenting with multiple extraintestinal manifestations of oral ulcerations, laryngeal ulceration, and coexisting psoriasis vulgaris. Recurrent oral ulcerations and skin lesions of psoriasis vulgaris were noted before the exacerbation of watery diarrhea and the diagnosis of CD. Laryngeal ulceration following GI symptoms was treated effectively with prednisolone therapy, while remission of CD was achieved via IFX administration.

CD lesions are focal with skipped areas of normal mucosa, and any part of the GI tract may be involved throughout the disease process (3). Laryngeal involvement of CD is rare and has been reported in 0.5-1.3% of cases, usually in young men (1). In another review of CD cases with laryngeal lesions, the patients were mostly young individuals in their 20s who had GI symptoms prior to laryngeal symptoms and had multiple extraintestinal manifestations of CD simultaneously (3). However, oropharyngeal lesions may precede GI symptoms in 26-60% of cases and resolve spontaneously in 25% of cases, regardless of GI lesion activity (1,4).

The diagnosis of oropharyngeal CD via a pathological examination may be difficult, as the incidence of noncaseating epithelioid cell granulomas varies from 10% to 75%, according to previous reports (1). In our case, group A streptococcal infection was noted; thus, the patient was initially treated with antibiotics. However, treatment failure with antibiotics suggested that the laryngeal ulceration resulted from inflammation other than bacterial infections. It was speculated that the streptococcal infection might be a secondary infection, including tonsilitis, or associated with the possibility of oropharyngeal bacterial flora causing the positive streptococcal test findings. Furthermore, the lack of improvement with hydrocortisone indicated that the etiologies were unlikely to be laryngopharyngeal injury or edema after tracheal intubation. Instead, the rapid treatment response to prednisolone led to the conclusion that the ulceration was related to the inflammatory pathogenesis of CD. A sore throat was noted soon after tracheal intubation, and mechanical irritation was suspected to provoke the onset or exacerbation of the laryngeal ulceration.

The differential diagnoses of laryngopharyngeal ulceration with concomitant IBD generally include tuberculosis, syphilis, Behçet's disease, sarcoidosis, lymphoma, and squamous cell carcinoma, among others (1,4,5). Infections can initially be ruled out via culture or a blood examination. Blood tests are also useful for screening for simultaneous occurrences of other autoimmune diseases. Biopsies are necessary if malignancy or other infiltrative/inflammatory diseases are suspected. Endoscopic findings may also play an important role in the diagnosis. Intestinal tuberculosis may present with a patulous ileocecal valve and can be diagnosed via an interferon gamma release assay or acid-fast staining. The absence of ileocecal ulcerations and other typical organ involvement, such as genital ulcerations and ocular lesions, may help rule out Behçet's disease (5). In our case, other endoscopic findings, such as non-contiguous irregular ulcerations in a longitudinal arrangement with normal surrounding mucosa, further supported the diagnosis of CD.

The treatment for oropharyngeal CD has not yet been determined. The new onset of oropharyngeal involvement in a patient with CD during adalimumab maintenance therapy has been previously reported (6), and successful treatment of oropharyngeal ulcerations with IFX or adalimumab has also been described (2,4). Remarkable and prompt resolution of laryngeal symptoms and lesions with systemic steroid therapy, such as oral prednisolone, has been reported (1,3,6). In our case, abdominal pain and inflammatory findings on blood tests resolved after the first infusion of IFX on day 8, while the laryngeal ulceration progressed. Furthermore, diarrhea was relieved soon after the second infusion of IFX on day 22, but sore throat and dysphagia persisted. It was not until the administration of prednisolone on day 25 that the laryngeal ulceration and symptoms showed sufficient improvement. The laryngeal ulceration responded to prednisolone instead of hydrocortisone because of the anti-inflammatory effect of the high glucocorticoid activity of prednisolone (7). In general, pharmacological doses of corticosteroids should be administered immediately, especially when airway obstruction is suspected (3).

In conclusion, extraintestinal manifestations may precede GI symptoms or occur at any time throughout the disease process of CD. The differential diagnosis should be made among infections and other infiltrative/inflammatory diseases. A histologic diagnosis may be difficult because of the variable detection rates of granulomatous lesions on biopsies. Systemic steroid therapy with prednisolone is considered effective for rapid symptom relief, especially in patients at risk for airway emergencies.

Author's disclosure of potential Conflicts of Interest (COI).

Fumihito Hirai: Lecture fees, Abbvie GK, EA Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, and Takeda Pharmaceutical.