Cutaneous Crohn’s disease after proctocolectomy for medically refractory colonic Crohn’s disease: a case series and review of the literature

Introduction

Cutaneous Crohn’s disease (CCD) is a rare form of extraintestinal Crohn’s disease (CD) consisting of granulomatous lesions that are non-contiguous with the gastrointestinal (GI) tract (i.e., separated from it by normal skin) [1]. CCD is considered a different entity than other cutaneous manifestations of CD, like those involving the skin at sites contiguous with the GI tract, such as perianal, peristomal, and peri-fistular inflammation, also characterized by granuloma formation [2]. In CCD, lesions have similar pathological findings to the ones found in the GI tract and contiguous skin lesions of CD patients, in addition to the presence of multinucleated giant cells, as well as a diffuse infiltrative pattern and a lack of acute inflammatory cells [3]. Clinically, CCD tends to have variable skin morphologies, including plaques, nodules, abscesses, and fistulas [4]. Rare but pathognomonic findings include “knife-life” fissuring and deep linear ulcers [5]. Although these lesions can manifest anywhere, they have a strong predilection for the moist environments of skin folds, including sub-mammary and abdominal creases as well as the perianal and inguinal regions [6]. It is noteworthy that the severity of these cutaneous lesions does not correlate with the severity of the luminal disease [6].

The onset of CCD in patients without active bowel disease, such as after proctocolectomy in colonic CD, is a particularly understudied phenomenon. It also carries significant challenges in terms of management, not only from a medical standpoint, but also breaking the news to patients that they may need to continue biologics after surgery. Less than 30 case reports in the literature have presented the onset of CCD post-subtotal or proctocolectomy in adults, and little has been studied about the association between this skin manifestation and the role of surgical intervention in their etiology. Herein, we report a case series of 4 patients with absent luminal CD who developed CCD, with a focus on the development of post-surgical CCD, and review the literature on this topic to find common characteristics that can predict CCD onset after proctocolectomy and the best-described management.

Patients and methods

This case series included 4 adult patients with CCD following proctocolectomy between January 2014 and December 2021 at our tertiary referral center. Baseline characteristics are demonstrated in Table 1A.

Table 1 (A) Characteristics of patients presenting with CCD after proctocolectomy

This study design was approved by the Institutional Review Board (IRB) at our hospital; given the observational and de-identified nature of the data, the requirement for a signed informed consent form was waived.

Literature review of CCD post-proctocolectomy

A comprehensive literature review was conducted by searching the PubMed and Embase databases from inception to December 2021 to identify all publications regarding CCD. The initial query identified 5,481 articles. Titles were revised, and those that discussed “cutaneous Crohn’s disease,” “metastatic Crohn’s disease,” and “cutaneous granulomatous skin lesions” were included. After verifying duplicate articles, the literature accounted for 410 studies. Of those, 29 were included based on the following inclusion criteria: 1) adult patients >18 years old; 2) biopsy-proven CCD; and 3) history of subtotal colectomy or total proctocolectomy. Table 1B demonstrates patients’ characteristics, skin areas affected, treatment prior to presentation with CCD (if any), and treatment after presentation that led to clinical response.

Table 1 (B) Summary of CCD cases after proctocolectomy reported in the literature

Case 1

A 49-year-old African American female with severe ileocolonic CD complicated by fistulizing perianal disease and perianal hidradenitis suppurativa (HS) who had a disease course refractory to medical therapy with infliximab (IFX) and azathioprine (AZA) and eventually underwent total proctocolectomy 4 years after her diagnosis. She remained in clinical remission while off medical therapy. She presented 6 years later with new “knife-cut” linear ulcerations in the groin area consistent with CCD, as demonstrated in Fig. 1A. The diagnosis was confirmed by pathology, which showed cutaneous ulceration with diffuse acute on chronic inflammation associated with loose granulomas involving the dermis and subcutaneous tissue, consistent with CCD. She was treated with a prolonged steroid tapering for 2 months and restarted on IFX every 8 weeks with significant improvement and stable condition at her 7-year follow up from therapy re-initiation (Fig. 1B). Her GI luminal disease remained quiescent on subsequent endoscopic and radiographic examinations. Few of the pathology slides are demonstrated in Fig. 1C-F.

Figure 1 (A, B) Patient 1: pre- and post-treatment of ulcerated, linear “knife-like” lesion in the right groin consistent with cutaneous Crohn’s disease (C, D, E, F) patient 1 pathology images: cutaneous ulceration with diffuse marked acute and chronic inflammation associated with loose granulomas, involving dermis and subcutaneous tissue consistent with cutaneous Crohn’s disease. (G, H) Patient 2: pre- and post-treatment of ulcerated, linear “knife-like” lesion in the gluteal cleft consistent with cutaneous Crohn’s disease. (I, J) Patient 3: pre- and post-treatment of erythematous fissured plaque with purulence in the gluteal cleft consistent with cutaneous Crohn’s disease. (K, L) Patient 4: pre- and post-treatment of a groin wound in cutaneous Crohn’s disease

Discussion

Cutaneous manifestations are reported in 22-44% of CD patients [34,35]. Cutaneous manifestations of CD are generally divided into 4 groups [36]: 1) cutaneous lesions as a direct extension of bowel disease such as oral, perianal, or peristomal skin lesions [37,38]; 2) reactive inflammatory dermatoses that do not share the same histopathological findings as CD but have a strong association with it, such as pyoderma gangrenosum (PG) and erythema nodosum (EN) [39]; 3) drug-related skin reactions [40]; and finally, 4) metastatic CD characterized by skin lesions that are noncontiguous with the GI tract and have similar sterile granulomatous inflammation histologically [39,41]. However, the term “metastatic” CD can be a misnomer since CD is not a malignancy, and these cutaneous lesions can occur before the onset of the GI disease or develop without any luminal involvement. Therefore, the term noncontiguous CCD would be more precise [5]. CCD is considered the rarest form of the skin manifestations of CD [42]. We present a case series and literature review of a unique subgroup of patients who had CCD onset in the setting of absent luminal CD, particularly after complete proctocolectomy or, theoretically, after removing the nidus of the inflammation.

The pathogenesis of CCD is still poorly understood. One proposed mechanism is the passage of an intestinal antigen to the skin triggering a subsequent granulomatous response at the level of the dermis [43-45]. Another suggested mechanism is antibody sensitization to gut antigens, possibly bacterial antigens, which then cross-react with analogous skin antigens [3,43]. Other authors suggested a T-lymphocyte mediated type IV hypersensitivity reaction to an unknown antigen in the skin leading to granuloma formation and potentially vascular damage resulting in secondary vasculitis [43]. Other hypotheses suggest that a multifactorial mechanism, including genetic factors, uninhibited immune reaction, altered enzymes, and bacterial reactions contribute to the pathogenesis of CCD [46]. It has been reported that elevated interleukin (IL)-23 expression was detected in dendritic cells as well as macrophages in CCD, suggesting that an intensified IL23/TH17 axis in addition to tumor necrosis factor (TNF)-α may play a vital role in the pathogenesis of CCD, similar to CD (47).

CCD has been identified in all age groups [44]. Some studies report that CCD affects men and women equally [46,48], whereas other reports in the literature suggest that women are more commonly affected compared to men [3]. Based on our observation in these case series, there was no correlation between the severity of these skin lesions and the activity of the luminal disease, and onset after a mean of 5 years from proctocolectomy. The clinical manifestations vary widely morphologically [49]. A strong predilection to moist environments in intertriginous areas has been documented [6]. When CCD affects such sites, it presents with an ulcerated “knife-like” fissuring and cuts, as shown in Fig. 1A, 1G, 1I, and 1K. Lesions on the extremities and face usually present with erythematous violaceus nodules or plaques that can be painful [46,48]. Generally, the most common areas affected are the genitals, legs, and face, as proven by a variety of case reports listed in Table 1B. Other less common areas reported in the literature include the breast, ear, and umbilicus [19,50,51].

Histological features of CCD are similar to those of the GI tract [52]. The dominant feature is an inflammatory infiltration with sterile non-caseating sarcoid-like granulomas with ample number of multinucleated giant cells (Langerhans giant cells) and plasma cells in the dermis and occasionally can extend into the subcutaneous tissue with a lack of acute inflammatory neutrophilic cells [3,35,46,48,52]. These granulomas can surround small and medium vessels and cause secondary vasculitis pattern [53-55]. This inflammatory perivascular reaction is attributed to the fact that CCD is related to circulating antigens into the dermis or perhaps due to immune complexes deposition within the skin layers [56]. Other less prevalent findings include collagen degeneration in the dermis called “necrobiosis” [55,57,58], eosinophilic infiltration with overlying epidermal ulceration, and lichenoid dermatitis [3].

CCD has been referred to as a great imitator both clinically and histologically [44]. As such, obtaining an accurate history, physical exam, considering other differential diagnosis, and most importantly performing a skin biopsy become very important. The differential diagnosis of CCD consists of any granulomatous inflammation that may involve the skin as demonstrated in Table 2. Histopathological findings are essential in differentiating these entities. For all granulomatous lesions, appropriate staining and cultures should be performed to rule out infectious etiologies.

Table 2 Differential diagnosis and their key differences from cutaneous Crohn’s disease [1,3,61,62]

One important distinction to make is differentiating HS from CCD as they can present in an overlap fashion and share common anatomical locations, specifically the anogenital region [59]. As both conditions can show similar histopathology with chronic inflammation and the presence of granulomas, clinical distinction is most critical. HS is fundamentally a disease of the hair follicle. Thus, while scarring can lead to sinus tract formation and ulceration, this is generally a sequela of chronic follicular inflammation beginning as an abscess. While pyoderma-like ulcerations can occur in areas of HS mimicking CCD, these generally develop over time and in association with a follicular unit. In CCD, this characteristic “knife-cut” fissures are an initial presentation and not anatomically tied to a hair follicle. In severe cases with overlap disease, it can be impossible to distinguish each lesion as there is likely shared pathophysiology between the entities. In our cases, clear knife-cut fissures were not associated with the hair follicle and were consistent with CCD rather than HS [60]. Another condition that poses a diagnosis dilemma is persistent perineal sinus syndrome after proctocolectomy for CD with possible overlap with CCD, as presented in case #3.

CCD carries significant morbidity and can have a negative impact on patients’ quality of life [6]. Although there is some evidence regarding the spontaneous resolution of these skin lesions, they are most likely to persist or even progress [56,63]. There is no consensus guideline regarding the best treatment approach for CCD [6,46]. Due to a lack of prospective studies and clinical trials in this domain, most evidence behind the available treatments is based on case reports and case series. A multidisciplinary approach to management, with close coordination between dermatology, gastroenterology, and colorectal surgery, is key to CCD management. Systemic steroids, such as high-dose oral prednisone or prednisolone, remain the cornerstone therapy to induce remission in the acute phase with a favorable clinical response [46,49,52,63]. Additionally, topical steroids such as betamethasone cream have been reported to result in the resolution of mild lesions [64]. Successful use of intralesional steroids has been reported as well [65]. Adding metronidazole to steroids in some cases has resulted in mixed outcomes [61,66]. In general, antibiotics such as oral ciprofloxacin or cephalosporines have been advocated for preventing infections and abscess formation but have no proven benefit [6,66]. A noteworthy efficacious therapy is topical tacrolimus 0.1% ointment, especially in perineal involvement [67]. Previously, Cyclosporine A was used with success in more severe CCD cases [11,13]. However, given its side effects profile and the availability of biologics, it has fallen out of favor. Immunomodulators like AZA, mercaptopurine (6-MP), and MTX have shown some promise when used as adjunct therapies to biologics. Konrad et al reported a case of recalcitrant CCD of the abdominal wall and bilateral sub-mammary folds that failed IFX therapy alone and only improved with the addition of MTX 15 mg weekly while continuing maintenance IFX [24]. Another non-traditional therapy is IVIG, used as a trial in case #3, which has been suggested in several reports to induce remission in fistulizing steroid-refractory CD but has not been studied in CCD [68].

The role of biologics in CCD appears promising based on the available evidence showing significant efficacy in severe cases. One caveat is recognizing paradoxical skin reactions related to TNF-α inhibitors, including anti-TNF-α-induced psoriasis, which are a separate category of cutaneous Crohn’s manifestations [69]. Additionally, patients may present with CCD while being on a TNF-α inhibitor and in complete remission of their luminal disease [70]. Therefore, high clinical suspicion is needed to make the diagnosis in such cases. There is one prospective study performed by Bhoyol et al, which included 31 women with a median age of 40 who had vulvar CD and were followed prospectively [71]. Eighty percent had active GI disease at the time of presentation. Topical therapies were effective in mild cases. Whereas TNF-α inhibitors were the most effective second-line therapy achieving complete clinical remission in 53% of patients. Since IFX was the first anti-TNF-α to be approved for IBD management, data supporting its use in CCD goes back 2 decades. IFX has shown encouraging results from several case reports in refractory CCD achieving clinical remission [72-74]. A case of diffuse and extensive CCD refractory to steroids, antibiotics, immunomodulators, and repeated surgical debridement reported by Miller et al, achieved rapid subjective and objective improvement with IFX 400 mg infusions used over 7 weeks [66]. Additionally, Yoong et al report one of the longest follow-up periods regarding CCD remission over 4.5 years on IFX [75]. This case series (cases #1 and #4) supports these results. Another TNF-α blocker, ADA, has shown efficacy in inducing and maintaining remission in CCD. Clinical remission has been reported by using ADA 40 mg injection biweekly in new-onset CCD concomitant with GI symptoms with rapid response achieving clinical remission within 6 weeks [76,77]. Additionally, Lazaro et al report a case of clinical remission of CCD after ADA dose escalation in a patient previously maintained on ADA for luminal GI disease [78]. Less data is available on CZP, a pegylated TNF-α blocker, with one case reporting complete resolution of CCD involving the lower extremities in a patient with known perianal CD and previous reaction to IFX [79]. All these encouraging results highlight the importance of future larger studies regarding the role of TNF-α inhibitors in CCD.

Ustekinumab, a monoclonal antibody against IL-12 and IL-23, is rising as a promising safe and effective treatment for CCD refractory to TNF-α blockers. Recent data showed that ustekinumab resulted in full clinical remission of severe recalcitrant CCD involving the vulva, perineum, gluteal, and facial regions within 7-28 months [7,10,31,80,81]. One case report suggests the use of 390 mg IV for 2 doses followed by the standard 90 mg injection every 8 weeks [80]. Our #2 case also corroborates those findings. Additionally, a meta-analysis including 22 studies showed that ustekinumab is a safe and effective treatment for all cutaneous manifestations of CD, including CCD [82]. However, comparative studies are lacking regarding the efficacy of its use compared to other biologics.

Although vedolizumab, a monoclonal antibody against α4β7-integrin, could have some efficacy in controlling extraintestinal manifestations in IBD [83], its role in CCD is unclear and perhaps less favorable. A multi-center case series study supported by the European Crohn’s and Colitis Organization (ECCO) assessed the role of vedolizumab vs. ustekinumab in the management of cutaneous manifestations of CD [84]. It included 28 patients, of which ten had CCD. Five achieved clinical remission on ustekinumab after 1-2 doses over a median follow up of 5 months. In contrast, only one patient improved on vedolizumab, suggesting that ustekinumab may be more useful in treating skin lesions in CD.

The role of surgery and hyperbaric oxygen therapy lack further evidence but have been shown to be effective in several case reports. Similar to luminal CD, surgical evaluation and input remain important in managing severe refractory CCD [14,27]. Williams et al report a case series of 6 patients with severe perineal CCD, who failed multiple lines of medical therapies, and underwent surgical management and debridement of their wounds. Five of them had a good clinical response and adequate cosmetic outcomes [85]. Moreover, the use of hyperbaric oxygen in addition to metronidazole has shown a dramatic improvement in severe perineal CCD within 3 months of treatment initiation in a case report by Brady et al [86]. In case #3, hyperbaric oxygen seemed to be beneficial when used in addition to biologics.

The association between colonic surgeries and CCD has not been studied and based on our observation, CCD can occur post-proctocolectomy and have variable disease course. A retrospective study by Roth et al evaluated the impact of colectomy on the extraintestinal manifestations of IBD and showed that almost half of the patients continue to have symptoms after surgery, and about 13% developed de novo manifestations after colectomy [87]. Although this study did not focus on cutaneous manifestations or CCD after colonic surgery per se, it supports our observation that resecting the initial nidus of the disease by performing proctocolectomy or APR may not prevent the occurrence of cutaneous disease.

It has been established that positive margins increase the risk of anastomotic recurrence after ileocecal resection for CD [88]. When proctectomy is performed in the setting of anorectal CD, the distal margin is frequently positive; the anal disease is often contiguous with the perianal tissues. In these cases, the perianal tissue is left in place and can potentially cause wound healing problems. Whether non-contiguous CD can be triggered from this tissue remains unclear.

Recent publications have suggested that the meso-colon and, possibly, the mesorectum, rather than the luminal intestinal tissue layers are driving the CD process [89,90]. Many surgeons perform a dissection between the mesorectum and the rectal wall when performing a proctectomy. This is done to minimize the post-surgical “dead space” in the pelvis and to decrease intestinal complications caused by bowel positioning and attaching itself deep in the pelvis. One recent retrospective review concluded that patients suffered a greater risk of perineal wound complications when the mesorectum was left in place [91]. There are ongoing trials comparing mesorectum sparing approaches to total meso-rectal excision techniques for proctectomy in CD patients. At this time, it is unknown whether mesorectum that has been left in the pelvis after proctectomy for CD could be a contributor to the development of CCD.

In summary, CCD is a rare condition that requires a complex treatment approach. Based on this case series, our group of patients developed CCD strictly in the perineal and gluteal regions after an average of 5 years post-proctocolectomy. Our suggested approach, demonstrated in Fig. 2, is to initiate a high-dose steroid course with a slow taper over 2-3 months, if there is no contraindication and after evaluation for possible superimposed infections, followed by an anti-TNF inhibitor (IFX was used in this case series) in combination with an immunomodulator. If there is no significant response despite therapy optimization, we suggest changing to ustekinumab and adding hyperbaric O₂ therapy for severe refractory wounds. Additionally, an early multi-disciplinary approach between Gastroenterology, Dermatology, Plastic Surgery, and Colorectal surgery is essential to achieve the best possible clinical outcome in these challenging cases.

Figure 2 Suggested algorithm for approach and management of cutaneous Crohn’s disease post-proctocolectomy

TNF, tumor necrosis factor; IL, interleukin