Cutaneous Crohn Disease Presenting as "Knife-Edged" Ulcers: A Case Report

© 2024 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Wounds or HMP Global, their employees, and affiliates.

Cutaneous findings are relatively common in patients with CD, with 1 study finding that nearly half of patients with CD (44.4%) had at least 1 cutaneous extraintestinal manifestation.¹ Cutaneous manifestations of inflammatory bowel disease are numerous, ranging from erythema nodosum to pyoderma gangrenosum and psoriasis.¹ CCD is typically divided into 3 categories: specific lesions, reactive lesions, and associated lesions. A fourth category described by some authors involves drug-induced skin lesions, most commonly from anti-TNF therapy.²

Specific lesions have histopathologic findings consistent with CD (eg, non-caseating granulomas). These lesions can be further divided into contiguous lesions, which are a direct extension from the intestine to the adjacent skin (perianal or peristomal sites), or metastatic CD, in which affected skin is not contiguous with the GI tract.^2,3 Unlike specific lesions, reactive lesions do not share the same histopathologic findings as CD despite having a similar pathogenesis.^1,2 The reactive lesions category includes conditions such as pyoderma gangrenosum and Sweet syndrome (acute febrile neutrophilic dermatosis).^1,2Associated lesions are thought to be either due to shared human leukocyte antigen-gene types or a result of chronic inflammation.² Erythema nodosum and oral lesions, such as aphthous ulcers, fall into this category.² In adults, 68.8% of CCD cases postdate the initial diagnosis of GI CD, 17.4% of cases occur simultaneously with GI CD, and 5.6% precede the onset of GI symptoms.³ In children, CCD is most likely to occur concomitantly with intestinal CD, occurring in 50.8% of cases.³ A minority of children present with cutaneous symptoms prior to their intestinal CD diagnosis (15.3%).³

A wide variety of therapeutic options for CCD have been described in the literature, including topical, intralesional, and systemic corticosteroids; antibiotics; immunosuppressants; immunomodulators; and surgery.⁴ However, they have mostly been described in the treatment of patients with concurrent luminal CD. There is no standard treatment algorithm for the management of refractory CCD with limited or covert GI involvement.

A 33-year-old female presented to the wound care clinic with chronic, nonhealing wounds on September 8, 2020. Skin examination revealed linear, "knife-edged" ulcerations involving the intertriginous spaces in the bilateral inframammary, inguinal, natal cleft, and axillary areas (Figures 1A-9A). The patient had a particularly complex medical history. She carried a presumed diagnosis of HS affecting the umbilicus, groin, and perineum starting in 2006. When she developed episcleritis in 2011, a periumbilical lesion was biopsied and histologic analysis revealed psoriasiform, superficial and deep perivascular, granulomatous, eroded dermatitis, suggesting CCD. A comment from the pathology report reads as follows:

Although histopathologic differential diagnostic considerations include granulomatous disorders of infectious etiology, special stains are negative for organisms. With respect to some of the granulomatous disorders of a non-infectious origin, polarization reveals no evidence of polarizable foreign material, and the presence of erosion would be unusual for sarcoidosis. Given the appropriate clinical context, the described findings are in keeping with cutaneous metastatic Crohn's disease, possibly without/prior to gastrointestinal involvement. There is neither evidence of acantholysis to suggest Hailey-Hailey disease (benign familial pemphigus)/pemphigus vulgaris nor subepidermal cleft formation to suggest bullous pemphigoid, and direct immunofluorescence studies are negative for immune complex deposition. The changes present are not in keeping with those of psoriasis itself. Specific features of necrolytic migratory erythema are not observed; the presence of granulomas would speak against the latter diagnosis.

Reports of subsequent esophagogastroduodenoscopy and colonoscopies performed in 2011, 2015, 2016, and 2018 describe nonspecific congestion and erythema in the colon and rectum, with no changes in the terminal ileum. Pathologically, however, the CD followed the patient's cutaneous symptoms with an approximately 9-year delay, with features of active GI disease (including granulomas and crypt distortion) evident by the time of the colonoscopy in 2015.

Over the years, the patient was treated with a variety of regimens. She did not clinically respond to treatments with antibiotics (doxycycline, metronidazole), immunomodulators (azathioprine, 6-mercaptopurine), and biologics (adalimumab, infliximab, certolizumab pegol, ustekinumab). The patient was maintained on chronic prednisone between 10 mg and 20 mg daily, up to 40 mg daily during flares. In addition to suboptimal control, additional dermatologic pathology complicated the case. The patient developed psoriatic lesions, thought to be a side effect of the TNF-α inhibitor, as well as biopsy-proven leukocytoclastic vasculitis, which was thought to be secondary to COVID-19 contracted in 2020.

The patient presented to the wound care clinic specifically for these intertriginous ulcers, which were long-standing, preceding her leukocytoclastic vasculitis diagnosis and previously attributed to HS. She reported occasional itching and burning sensation at the sites, as well as persistent clear drainage. Because her wounds had been present for over a decade, a biopsy was recommended to rule out neoplastic transformation and to aid with the diagnosis. Incisional biopsies of her right axilla and right groin wounds were performed on November 10, 2020, and sent for histopathologic evaluation.

Microscopic analysis of the right axillary lesion revealed diffuse, non-caseating granulomatous dermatitis with marked lymphoplasmacytic infiltrates with stromal hemorrhage (Figure 1B, C). Biopsy of the groin lesion demonstrated cutaneous ulceration with knife-edge fissures extending deep into the dermis, underlined by fibrinoid necrotizing capillaritis and abscess formation (Figure 2B). Special stains did not reveal infectious agents. Polarizable or refractile foreign material was not detected. Based on these distinct histologic findings and the clinical history, the diagnosis of CCD was reconfirmed.

In addition to receiving care in the wound care clinic, the patient continued to follow up with specialists in gastroenterology and rheumatology. Her cutaneous disease was refractory to treatment until monthly IVIG infusions were initiated. To wean the patient off steroids, she was started on methotrexate and hydroxychloroquine. Concomitant with the medical regimen, wound care included treatments with energy-based modalities by specialists in the wound care physical therapy department consisting of electrical stimulation for 45 minutes (1 wound per session), high-frequency ultrasound (treatment time dependent on area treated), and ultraviolet C light (30 seconds per area treated) 3 times weekly and various topical agents (silver alginate, then topical tacrolimus with collagen dressing, then antimicrobial wound gel [BLASTX; Next Science] with collagen powder).

A surveillance colonoscopy in April 2022 did not reveal evidence of inflammatory bowel disease. As of this writing, complete closure of the wounds in both axillae, inframammary folds, and bilateral inguinal areas has been achieved (Figure 3-8), and the remaining lesion in the natal cleft exhibits a positive healing trajectory and is expected to fully heal (Figure 9B).

The current study discusses a case of CCD presenting as long-standing intertriginous, knife-edged ulcerations in the setting of initially absent and then minimal GI involvement. For a disease in which GI pathology is the hallmark, the dermatologic symptoms and visible pathology of the patient reported herein dwarfed the changes in her GI tract. Furthermore, multiple therapies were unsuccessful, but the patient responded to IVIG. To the knowledge of the authors of the current report, this is the first description of refractory CCD responsive to IVIG.

CCD may be challenging to recognize in a patient without an established history of luminal CD given the variety of clinical presentations and the differential diagnosis for these nonspecific skin lesions. CCD commonly presents as linear or knife-edged ulcers in the intertriginous skin, as described in the current case. Genital involvement is more common in children (about 90% of child CCD cases) than in adults (up to 60% of adult CCD cases).³ Other potential clinical manifestations include erosions, dusky plaques, subcutaneous sinus tracts, and ulcerations with undermined edges.⁴ The differential diagnosis for intertriginous ulcers includes CCD, HS, CS, intertrigo, herpes simplex virus infection in an immunocompromised patient, Langerhans cell histiocytosis in a pediatric patient, and Beçhet disease.^3,5,6

Histopathologically, CCD consists of nodular, non-caseating epithelioid granulomatous lesions with surrounding lymphocytes, plasma cells, and scattered multinucleated Langerhans-type giant cells involving the superficial and deep dermis and can extend into the subcutaneous layer.⁴ Such histologic findings can mimic sarcoidosis. Although the granulomas of CCD are difficult to distinguish from the granulomas of CS, the presence of epidermal ulceration, eosinophilic infiltrate, and dermal edema seen in CCD are helpful features to differentiate the 2 entities.⁵ Specific diagnostic criteria for CCD have not yet been established in the literature.

Granulomatous skin lesions are generally divided into infectious and noninfectious granulomas. Other causes of noninfectious cutaneous granulomas, besides CCD and CS, include granuloma annulare, necrobiosis lipoidica, rheumatic nodules, foreign body granulomas, and interstitial granulomatous dermatitis.⁷ Granuloma annulare is the most common type of cutaneous granuloma, with a predilection for patients younger than 30 years. This condition most commonly occurs on the extremities and presents clinically as small, well-defined papules that form annular erythematous to flesh-colored plaques.⁷ In contrast, necrobiosis lipoidica is a rare chronic granulomatous dermatitis that is often associated with diabetes but may present in the absence of diabetes. Clinically, this condition presents as a well-defined oval plaque with a raised erythematous border and reddish-brown center, which later becomes yellow and atrophic.⁷ Interstitial granulomatous dermatitis is a rare condition with a heterogeneous clinical presentation and an association with systemic autoimmune diseases, such as rheumatoid arthritis, scleroderma, and lupus. Historically, this condition was described as subcutaneous linear nodules, termed the "rope sign"; various other clinical descriptions have been noted, however, including erythematous papules, subcutaneous plaques, annular lesions, and reddish-purple nodules.⁷ Cutaneous granulomas represent a variety of conditions, often of infectious, metabolic, or inflammatory origin, which contributes to their challenging diagnosis.⁷

CCD can cause significant morbidity and affects nearly half of all patients with CD.^1,8 A treatment algorithm for the management of CCD is evolving. The authors of the current case report propose an escalating stepwise approach as demonstrated in Figure 10. It is recommended that patients with CCD begin treatment with high-potency topical steroids (eg, betamethasone valerate 0.1% cream, betamethasone dipropionate 0.05% cream, or clobetasol propionate 0.05% cream applied 2 to 3 times daily) or topical tacrolimus.^4,9-15 If within 4 to 8 weeks this treatment is rendered ineffective, then a 4-month trial of metronidazole (800mg–1.2g daily)^16-18 and prednisone (20 mg–40 mg daily)^17–22 can be initiated. Immunomodulators and TNF-α inhibitors have also been shown to play a role in the treatment of patients with CCD.¹⁴ Case reports describe success with cyclosporine 3.5-4mg/kg/day or 250mg twice daily,^23-25 azathioprine 2mg/kg,⁹ 6-mercaptopurine,²⁶ infliximab,^18,27,28 infliximab combined with methotrexate,²⁹ certolizumab,³⁰ and adalimumab.^31,32 The lesions of the patient in the current case report were particularly challenging to treat, requiring multiple treatment modalities. While IVIG has shown promise for managing medically refractory CD,^33,34 to the knowledge of the authors of the current case report, this is the first reported instance of managing CCD with IVIG. Although CCD is often refractory to treatment, cases of spontaneous healing have occurred.³⁵

A multidisciplinary approach is essential for the successful treatment of patients with CCD. The medical team should include specialists in rheumatology, internal/family/pediatric medicine, dermatology, wound care, infectious diseases, dermatopathology, and gastroenterology. Psychological and physical disability caused by CCD should be emphasized. Involvement of a specialist in psychology or psychiatry may be valuable in the management of depression, anxiety, and social isolation. Such patients frequently require assistance with coping techniques as well as treatment with antidepression and antianxiety medications.^36,37

This report has limitations. It includes a single case, and each patient may react differently to the therapies discussed in this report. Furthermore, as of this writing this patient is being treated with a multimodal approach, which makes it difficult to ascertain the single most effective therapy. The treatment algorithm presented herein is based on published case reports and clinical experience, because large-scale randomized studies are unavailable. It can be difficult to confirm a diagnosis of CCD, because it can mimic so many other conditions. Many of the therapeutic agents discussed in this case report may be of value in managing other immune-related conditions, such as CS.³⁸

The purpose of the current case report is to raise awareness that CCD can mimic other skin conditions, such as CS and HS. In cases of isolated CCD with limited GI involvement, pathologists and clinicians are faced with a diagnostic challenge. It is important to include CCD in the differential diagnosis of a patient with knife-edged granulomatous skin lesions in intertriginous locations. Thus, along with obtaining tissue biopsies, timely referral to various specialists is essential for expeditious diagnosis and successful management. The authors of the current report provide a potential treatment algorithm to guide clinicians in managing this difficult clinical condition and encourage additional research on this disease to further tailor the treatment algorithm.

Authors: Melissa A. Nickles, MD¹; Saman S. Karimi, MD, MS²; Heidi Kurn, DO³; Marylee Braniecki, MD²; Anne Polick, MD⁴; Itishree Trivedi, MD, MS⁵; Nadera Sweiss, MD⁶; and Igor A. Altman, DO⁷

Affiliations: ¹Department of Dermatology, University of Illinois at Chicago, Chicago, IL; ²Department of Pathology, University of Illinois at Chicago, Chicago, IL; ³Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL; ⁴Department of Internal Medicine, University of Illinois at Chicago, Chicago, IL; ⁵Department of Gastroenterology, University of Illinois at Chicago, Chicago, IL; ⁶Department of Rheumatology, University of Illinois at Chicago, Chicago, IL; ⁷Department of Surgery, University of Illinois at Chicago, Chicago, IL

Disclosure: The authors disclose no financial or other conflicts of interest. 

Correspondence: Igor Altman, DO; Department of Surgery, Section of Wound Healing and Tissue Repair, University of Illinois Hospital and Health Sciences System, 840 S. Wood Street, Suite 376 CSN, Chicago, IL 60612; ialtman@uic.edu

Manuscript Accepted: January 24, 2024