BASIC/CLINICAL SCIENCE
Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study Adam V. Weizman, Brian Huang, Stephan Targan, Marla Dubinsky, Phillip Fleshner, Manreet Kaur, Andrew Ippoliti, Deepa Panikkath, Eric Vasiliauskas, David Shih, Dermot P.B. McGovern, and Gil Y. Melmed Background: Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). Objective: To better characterize PG features and management among an IBD cohort. Methods: Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. Results: Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. Conclusions: We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients. Contexte: La pyodermite phage´de´nique (PP) est une manifestation extra-intestinale grave d’une maladie inflammatoire chronique de l’intestin (MICI). Objectif: L’e´tude visait a` bien caracte´riser les manifestations de la PP et a` en ame´liorer la prise en charge au sein d’une cohorte souffrant de MICI. Me´thode: La recherche de sujets atteints de PP s’est faite dans une base de donne´es importante, rattache´e a` un centre de soins tertiaires. Les donne´es de´mographiques et les caracte´ristiques cliniques ont e´te´ re´sume´es a` l’aide de statistiques descriptives. Re´sultats: Ont ainsi e´te´ repe´re´s 80 patients ayant souffert d’un ou de plusieurs e´pisodes de PP, ce qui a porte´ a` 1,9% la pre´valence ge´ne´rale. Dans l’ensemble, 93% des patients atteints de PP souffraient, jusqu’a` un certain point, d’une inflammation du coˆlon. Trente et un (39%) d’entre eux ont duˆ eˆtre hospitalise´s pour une PP. Une affection sous-jacente de l’intestin e´tait en phase e´volutive au moment de l’e´pisode de PP chez 52 (65%) patients. Le sie`ge de la PP e´tait variable, mais les membres infe´rieurs e´taient le plus souvent touche´s. La cicatrisation de la PP a ne´cessite´ de nombreux traitements chez la plupart des patients (71.3%). Conclusions: Il s’agit la` de l’une des plus grandes se´ries de cas de PP, de´crits parmi des patients atteints de MICI. La diversite´ des strate´gies de traitement fait bien ressortir le manque de lignes de conduite claires relativement a` la prise en charge de la PP dans ce groupe de patients difficiles a` traiter.
YODERMA GANGRENOSUM (PG), a neutrophilic dermatosis affecting the skin, is one of the more common extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD).1–4 The lesion of PG usually begins as a papule or pustule at a site of trauma with a surrounding violaceous and undermined border,5 with subsequent necrosis of the dermis resulting in deep ulcers as the lesion progresses. PG is characterized by pathergy and most commonly occurs on the legs, but lesions can occur anywhere (eg, adjacent to stoma).6,7 PG occurs in 0.5 to 5% of patients with IBD and has previously been shown to be more common in women and IBD patients with other EIMs and has also been
P
From the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Women’s College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ON; Department of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CA; and Medical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA. Address reprint requests to: Gil Y. Melmed, MD, 8730 West Alden Drive Thalians 2E, Los Angeles, CA 90048; e-mail: [email protected].
DOI 10.2310/7750.2014.14053 # 2014 Canadian Dermatology Association
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particularly associated with ulcerative colitis (UC) and among patients with colonic Crohn disease (CD).7–11 The development of PG is one of the more severe EIMs of IBD, with the potential for both significant morbidity and tremendous impact on activities of daily living and quality of life.5,6 Severe disease can be cosmetically disfiguring and may lead to permanent scarring, significant pain, bacterial superinfection, and skin grafting. Moreover, potent immunosuppression with therapeutic agents such as intravenous cyclosporine or anti–tumor necrosis factor (anti-TNF) agents may be needed, independent of underlying intestinal disease activity.7,12,13 Due to the relative rarity of this condition, there are a limited number of published large, IBD cohorts with PG. In this report, we review a large, well-phenotyped IBD cohort with the aim of better characterizing the clinical features, underlying disease characteristics, and management strategies of PG.
Materials and Methods Subjects Subjects with PG were identified using our longitudinal IBD database, which contains detailed clinical (demographics, disease phenotype, disease history, EIMs, treatment record), serologic, and genetic data on over 4,000 patients with IBD. Medical records of patients identified as having one or more episodes of PG between the years 1997 and 2012 were reviewed to confirm and better characterize the PG episode(s) and underlying IBD. Clinical data collected included demographics (age, gender, ethnicity, race), family history, disease duration, disease phenotype (IBD subtype and disease location/behavior according to the Montreal Classification14), surgical history, treatment record, smoking status, and the presence or absence of other EIMs. IBD disease activity at the time of a PG episode was determined retrospectively by the presence of symptoms and, when available, elevated inflammatory markers, fecal calprotectin, and endoscopic correlation.
Case Definition An episode of PG was defined based on either dermatology consultant impression or a dermatologic lesion with three or more of the following typical clinical features15: (1) leg or peristomal location; (2) pathergy; (3) initial pustular lesion; (4) purulent discharge; (5) violaceous or undermined borders; (6) crater-like holes/cribriform scarring. 126
Histology reports were reviewed, when available, to exclude alternative diagnoses. Statistical Analysis Patient demographics and clinical characteristics were summarized using descriptive statistics. Ethical Considerations The study was approved by our Institutional Research Board (IRB), and all subjects provided written, informed consent when initially enrolled into the IRB-approved database.
Results Demographics We identified 104 patients from the database with at least one episode of PG. Among these, 24 did not meet our above criteria for defining PG, and it was determined that they did not have PG and were therefore excluded. Thus, 80 patients with a confirmed episode(s) of PG were included in this case series. At the time of the study, the database contained information on 4,137 patients, yielding an overall prevalence of PG among this tertiary care population of 1.9%. Table 1 outlines the demographic characteristics of the 80 patients with at least one episode of PG. Fifty-eight (73%) had CD, 19 (24%) had UC, and 3 had IBD-unclassified. Overall, 46 (58%) were female and 34 (42%) were male. Sixty-nine (86%) were of northern European origin. The mean age at IBD onset was 31 6 14.5 years. Twenty-four (30%) patients reported a positive family history of IBD. Thirty-one (39%) patients were former or current smokers at the time of IBD diagnosis. Fifty-three (66%) patients had experienced at least one other EIM. The majority of patients had previous exposure to corticosteroids (93%), 5aminosalicylic acid (5-ASA) or sulfasalazine (84%), immunomodulators (96%), or a biologic (85%). Colonic and ileocolonic disease were most common among those with CD (43% and 45%, respectively), and extensive colitis was most common among those with UC (85%). Overall, 93% of patients with PG had some degree of colonic inflammation. PG Characteristics Dermatology consultation was obtained in 31 (39%) cases, with 21 (26%) patients undergoing biopsy of the lesion,
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Table 1. Clinical and Demographic Characteristics of the IBD-PG Cohort PG Subjects Clinical/Demographic Feature Female Male Crohn disease Ulcerative colitis IBD-unclassified Disease reclassification Mean age at IBD onset (yr) 6 SD Smoking history Family history of IBD Previous IBD-related surgery Previous medication use Corticosteroids 5-ASA Immunomodulator* Cyclosporine Biologic{ Other{ Other EIM Oral ulcers Ophthalmologic Arthritis Sacroiliitis/ankylosing spondylitis Erythema nodosum PSC
n (% of overall cohort) 46 (58) 34 (42) 58 (73) 19 (24) 3 (3) 21 (26) 31 6 14.5 31 (39) 24 (30) 51 (64) 74 67 77 16 68 3 53 12 12 24 3
(93) (84) (96) (20) (85) (4) (66) (15) (15) (30) (, 1)
11 (14) 1 (, 1)
5-ASA 5 5-aminosalicylic acid; EIM 5 extraintestinal manifestation; IBD 5 inflammatory bowel disease; PG 5 pyoderma gangrenosum; PSC 5 primary sclerosing cholangitis. * 6-Mercaptopurine, azathioprine, methotrexate. { Infliximab, adalimumab, certolizumab, natalizumab. { Others include thalidomide.
and the remaining cases being diagnosed clinically. The mean age at onset of the first episode of PG was 39.3 years. The majority of patients had only one episode of PG (61 [76%]). Twelve (15%) patients had two to three episodes, and 7 (9%) had more than three episodes. Underlying IBD was active at the time of the PG episode(s) in 52 (65%) patients. Four patients developed PG several years before the onset and diagnosis of IBD. The location of the PG was variable (Table 2), with the most common sites being the lower extremity (53% with unilateral leg inflammation and 19% with bilateral leg inflammation). Peristomal PG was noted in 23% (18) of patients. Less common sites included the trunk, upper extremity, face (Figure 1), scalp, and perianal or pubic region (Figure 2).
Table 2. Features of Pyoderma Gangrenosum PG Subjects PG Feature
n (% of PG cohort)
Age at first PG episode IBD active at onset Number of PG episodes 1 2–3 .3 Location* Unilateral lower extremity Bilateral lower extremity Peristomal area Trunk Back Upper extremity Face Perianal area Pubic area Scalp
39.8 52 (65) 61 (76) 12 (15) 7 (9) 42 15 18 5 4 5 3 1 1 1
(53) (19) (23) (6) (5) (6) (4) (1) (1) (1)
IBD 5 inflammatory bowel disease; PG 5 pyoderma gangrenosum. * Patient may have had PG at more than one site.
Therapy A variety of therapeutic approaches were used for treating PG in this cohort. Most patients (71.3%) required multiple therapies to achieve PG healing, whereas the remaining patients were managed with a single agent. Six (8%) patients received no treatment. Thirty-one (39%) patients
Figure 1. Severe facial pyoderma gangrenosum. Note full-thickness ulceration with visualization of underlying dentition and characteristic ‘‘heaped-up’’ edges with a violaceous border. This lesion healed with a combination of cyclosporine, intravenous immunoglobulin, and hyperbaric oxygen treatments.
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Figure 2. Perianal pyoderma gangrenosum in a patient with ileal pouch-anal anastomosis. These lesions healed with intravenous corticosteroids and cyclosporine.
required hospitalization for a PG episode. At the time of PG onset, 10 (13%) were actively on an anti-TNF agent for the treatment of their underlying IBD. Systemic corticosteroids were the most commonly prescribed therapy, with 47 (59%) patients receiving either oral or intravenous steroids at some point during the PG episode. Intralesional injection of corticosteroids was used in 9 (11%) patients. Anti-TNF agents and cyclosporine were used in the treatment of PG with equal frequency (29%). Azathioprine was used as an adjuvant treatment in 6 (8%) patients. Hyperbaric oxygen was used in 3 (4%) patients, and intravenous immunoglobulin was used in 1 patient. Surgical intervention was part of the management of 16 (20%) patients. This included skin grafting, tissue de´bridement, and/or resiting of stoma. Four (5%) patients were managed exclusively with surgical intervention and did not receive any specific medical therapy for PG.
Discussion PG is a severe EIM of IBD, with lesions having significant pain and scarring and patients often requiring hospitalization. Moreover, PG management often requires aggressive immunosuppressant therapy, even in the absence of active underlying IBD. The current study aimed to characterize the clinical and dermatologic features of a large IBD patient cohort followed at a tertiary referral center with at least one episode of PG. We noted 80 cases of PG among the cohort, yielding a prevalence of 1.9%. This is in agreement with other published series in which the prevalence of PG has ranged 128
from 0.5 to 5%.8–11,16 Among our cases, 73% had CD, although previous studies have not consistently demonstrated a clear association between a particular IBD subtype with PG. PG was more commonly found in patients with UC in a large population-based Swiss cohort,16 whereas in a population-based cohort from Manitoba, PG was more prevalent in CD,10 and this finding has subsequently been supported by others.17 Our results may be, in part, a reflection of a higher incidence of CD in the patients seen at our center, and it is important to note that this cohort is a tertiary referral center–ascertained cohort, in contrast to the Swiss and Manitoba-based studies above. Although data on IBD subtype are conflicting, there is more consistency among studies evaluating IBD disease location and association with PG. Colonic disease has previously been associated with several EIMs, including PG, erythema nodosum, and IBD-associated arthritis.7–18 We similarly noted that colonic and ileocolonic disease was most common among those with CD (43% and 45%, respectively), and extensive colitis was most common among those with UC (85%). Overall, 93% of patients had some degree of colonic inflammation. The predominance of colonic disease in subjects with EIM suggests underlying mechanisms intrinsic to colonic inflammation, which may include genetic, immunologic, and/or microbiologic interactions such as cross-reactivity of skin, joint, and eye and gut antigens.19 This intriguing overlap and potential link are further supported by the association between perinuclear antineutrophil cytoplasmic antibodies (pANCAs), a serologic marker often detected in patients with colonic IBD, including UC and UC-like CD phenotypes,20 with a number of EIMs, such as uveitis.21 In addition genetic variation at the major histocompatibility complex has previously been associated with both extensive colonic disease and the presence of EIMs.22 We noted a slight female predominance (58%) among our PG cohort. Several studies have previously noted an association between EIMs and female gender, including a Swedish study that found that erythema nodosum was more than three times more likely to occur in women.18 In addition, Vavricka and colleagues noted an EIM prevalence of 50% in females compared to only 34% in males (p , .001).16 A female predilection for PG is less clear from the literature. A recent systematic review identified 60 cases of PG, 55% of whom were female.7 The findings of female predominance suggest a possible role of hormonal influences, and some have suggested that estrogen may have a modulating effect on EIMs.23 Clearly, more study is needed to explain these observed gender differences. The literature suggests that patients with one EIM are more likely to develop additional EIMs.16–18 For example,
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Vavricka and colleagues observed that patients with IBDassociated arthritis had an odds ratio of 2.9 for subsequent PG development.16 We noted that two-thirds of patients with PG had either a previous history of EIM or subsequently developed another EIM. IBD-associated arthritis was the most common other EIM noted in our cohort. These findings point to a common underlying pathophysiology for EIMs in IBD, suggesting a need for further study to better define the apparent common etiology in CD. We noted a mean age at first episode of PG onset of 39 years. This age is somewhat younger compared to other series, in which the age of PG diagnosis ranged from 45 to 62 years.23–27 However, these published cases were not necessarily limited to patients with IBD and so included patients with PG associated with hematologic disorders, for example, which are more commonly seen in older individuals. An IBD-specific cohort found an age at PG onset of 36 years, similar to our results.17 The relationship between PG onset or recurrence and underlying IBD disease activity is unclear. Traditionally, PG behavior and IBD disease activity were thought to follow independent courses, with approximately half of patients having active disease at the time of PG onset.6 A more recent study noted that 75% of patients with PG onset had active disease.28 We found that approximately two-thirds of patients had active IBD at the time of PG onset. These findings suggest that the association between disease activity and PG is stronger than previously reported. More prospective studies objectively evaluating disease activity at the time of PG development are needed to better characterize the influence of active intestinal inflammation on PG, as has been shown with other EIMs, such as erythema nodosum.28 Although PG location was variable, the leg was the most common site, with 57 episodes of PG involving the lower extremity either unilaterally or bilaterally. The propensity for the lesion to form on the lower extremity is consistent with most other reports evaluating PG characteristics.1,5–7,15 Pathergy, the development or worsening of a lesion after trauma, is a classic characteristic of PG and may be responsible for the high incidence of lesions on the leg as this is a high-risk area for minor injuries.15 This phenomenon may also explain the finding of peristomal pyoderma as minor trauma to the area with appliance changes is common. We noted 15 episodes of peristomal pyoderma, making it the second most common site for PG development, similar to previous reports.15,17,25 Several patients had multiple concurrent lesions, and although most had only one episode of PG, nearly one-quarter of patients had multiple episodes over time. Some have
recommended a more aggressive management approach for patients with multilesional PG, citing a greater tendency for lesions to progress when present in more than one location.29 A number of less commonly encountered sites were also observed, including the face (see Figure 1) and perianal area (see Figure 2). Whether multifocal PG or the occurrence of a lesion on an atypical site carries a worse prognosis needs to be further elucidated. A variety of therapies were used in the management of PG among our cohort. The finding that over 70% of patients required multiple treatments to achieve PG healing and that approximately 40% of patients required hospital admission specifically for the management of PG underscores the severe nature of many of these PG episodes. Systemic corticosteroids were the most commonly used treatment, with nearly 60% of patients receiving intravenous or oral corticosteroids. Only 11% were treated with topical or intralesional steroids, a lower figure than most other reports,26,27 suggesting that cases among our cohort were considered too severe for local therapy. Although no controlled studies for corticosteroids are available, many reports have shown their efficacy, and they are therefore considered by many to be first-line therapy for PG.29–31 A notable exception was a report by Vidal and colleagues, in which cyclosporine was more commonly used and more effective than corticosteroids, leading the authors to conclude that cyclosporine should be first-line treatment for the induction of rapid wound healing.27 Four percent of patients received hyperbaric oxygen for treatment, usually as an adjuvant therapy for severe cases. Just under one-third of our cohort received intravenous cyclosporine, usually together with systemic steroids. Most of these patients started cyclosporine after failing to improve after several days of intravenous steroids. This practice is supported by a small prospective cohort of 11 patients who were treated with cyclosporine after failing steroid monotherapy, whereby 100% achieved complete wound healing, with a mean time to healing of 1.4 months.12 Moreover, the authors noted that patients transitioned to azathioprine had no recurrence, a practice that was uncommon in our cohort, with only six patients started on azathioprine as PG therapy. Twenty-nine percent of patients were started on anti-TNF therapy in the management of PG. As with patients started on cyclosporine, these patients were largely steroid monotherapy failures. Interestingly, 13% of patients were already on anti-TNF therapy at the time of PG onset. This may suggest a unique mechanism of PG development in this subset of patients
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given that anti-TNF has been demonstrated to heal PG in a small randomized controlled trial and a number of small case series.13–32 A similar parallel has been noted with psoriasis, a dermatologic lesion also treated with anti-TNF therapy. Lesions erupting paradoxically following anti-TNF therapy have been described in a subset of IBD patients.33,34 Uncontrolled interferon-a levels in the setting of TNF inhibition are one hypothesis for a mechanism underlying this paradoxical finding.35 More studies on the underlying pathophysiology and immunologic underpinnings of PG are needed to better clarify optimal treatment regimen(s). A number of limitations in the current study are noted. First, the retrospective nature of this study limited the ability to collect standardized information. The quality of the description of PG lesions and associated therapy was variable, a well-recognized shortcoming of retrospective reviews of this relatively rare condition. Important treatment details, including efficacy and time to healing, were not consistently documented and were therefore not reported. A standardized approach for monitoring the clinical course of PG is therefore needed. Moreover, assessing IBD disease activity retrospectively relies on objective assessments available in the medical record at that time (eg, endoscopic reports, fecal calprotectin, inflammatory markers). Assessment of disease activity was not always formally assessed at the time of new PG diagnosis. Second, our case definition was limited by the fact that no validated definition of PG is available. However, we used the descriptive, clinical criteria cited by most authors; therefore, our definition is well aligned with other reports in the literature. Third, our cohort consisted of severe cases of PG followed at a tertiary IBD referral center and therefore likely reflects more severe cases and limits the generalizability of our findings to other settings. However, despite these limitations, we describe one of the largest case series of PG in a well-characterized cohort of patients with IBD. Hospitalization was not uncommon, underscoring the morbidity and cost associated with this severe EIM. Moreover, a variety of treatment strategies were used, highlighting the lack of clear guidelines as to how to effectively manage this complex group of patients. More study on the clinical characteristics of PG complicating IBD is needed, as well as on the underlying genetic and immunologic underpinnings of this debilitating dermatologic manifestation.
Acknowledgments Financial disclosure of authors: Gil Y. Melmed, MD acts as a consultant for AbbVie, Jannsen, UCB, Celgene, Given 130
Imaging, Luitpold Pharmaceuticals. He also received grant support from Prometheus labs and Pfizer. Financial disclosure of reviewers: None reported.
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Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study Adam V. Weizman, Brian Huang, Stephan Targan, Marla Dubinsky, Phillip Fleshner, Manreet Kaur, Andrew Ippoliti, Deepa Panikkath, Eric Vasiliauskas, David Shih, Dermot P.B. McGovern, and Gil Y. Melmed Background: Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). Objective: To better characterize PG features and management among an IBD cohort. Methods: Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. Results: Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. Conclusions: We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients. Contexte: La pyodermite phage´de´nique (PP) est une manifestation extra-intestinale grave d’une maladie inflammatoire chronique de l’intestin (MICI). Objectif: L’e´tude visait a` bien caracte´riser les manifestations de la PP et a` en ame´liorer la prise en charge au sein d’une cohorte souffrant de MICI. Me´thode: La recherche de sujets atteints de PP s’est faite dans une base de donne´es importante, rattache´e a` un centre de soins tertiaires. Les donne´es de´mographiques et les caracte´ristiques cliniques ont e´te´ re´sume´es a` l’aide de statistiques descriptives. Re´sultats: Ont ainsi e´te´ repe´re´s 80 patients ayant souffert d’un ou de plusieurs e´pisodes de PP, ce qui a porte´ a` 1,9% la pre´valence ge´ne´rale. Dans l’ensemble, 93% des patients atteints de PP souffraient, jusqu’a` un certain point, d’une inflammation du coˆlon. Trente et un (39%) d’entre eux ont duˆ eˆtre hospitalise´s pour une PP. Une affection sous-jacente de l’intestin e´tait en phase e´volutive au moment de l’e´pisode de PP chez 52 (65%) patients. Le sie`ge de la PP e´tait variable, mais les membres infe´rieurs e´taient le plus souvent touche´s. La cicatrisation de la PP a ne´cessite´ de nombreux traitements chez la plupart des patients (71.3%). Conclusions: Il s’agit la` de l’une des plus grandes se´ries de cas de PP, de´crits parmi des patients atteints de MICI. La diversite´ des strate´gies de traitement fait bien ressortir le manque de lignes de conduite claires relativement a` la prise en charge de la PP dans ce groupe de patients difficiles a` traiter.
YODERMA GANGRENOSUM (PG), a neutrophilic dermatosis affecting the skin, is one of the more common extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD).1–4 The lesion of PG usually begins as a papule or pustule at a site of trauma with a surrounding violaceous and undermined border,5 with subsequent necrosis of the dermis resulting in deep ulcers as the lesion progresses. PG is characterized by pathergy and most commonly occurs on the legs, but lesions can occur anywhere (eg, adjacent to stoma).6,7 PG occurs in 0.5 to 5% of patients with IBD and has previously been shown to be more common in women and IBD patients with other EIMs and has also been
P
From the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Women’s College Hospital, Division of Gastroenterology, University of Toronto, Toronto, ON; Department of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, CA; and Medical Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, CA. Address reprint requests to: Gil Y. Melmed, MD, 8730 West Alden Drive Thalians 2E, Los Angeles, CA 90048; e-mail: [email protected].
DOI 10.2310/7750.2014.14053 # 2014 Canadian Dermatology Association
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particularly associated with ulcerative colitis (UC) and among patients with colonic Crohn disease (CD).7–11 The development of PG is one of the more severe EIMs of IBD, with the potential for both significant morbidity and tremendous impact on activities of daily living and quality of life.5,6 Severe disease can be cosmetically disfiguring and may lead to permanent scarring, significant pain, bacterial superinfection, and skin grafting. Moreover, potent immunosuppression with therapeutic agents such as intravenous cyclosporine or anti–tumor necrosis factor (anti-TNF) agents may be needed, independent of underlying intestinal disease activity.7,12,13 Due to the relative rarity of this condition, there are a limited number of published large, IBD cohorts with PG. In this report, we review a large, well-phenotyped IBD cohort with the aim of better characterizing the clinical features, underlying disease characteristics, and management strategies of PG.
Materials and Methods Subjects Subjects with PG were identified using our longitudinal IBD database, which contains detailed clinical (demographics, disease phenotype, disease history, EIMs, treatment record), serologic, and genetic data on over 4,000 patients with IBD. Medical records of patients identified as having one or more episodes of PG between the years 1997 and 2012 were reviewed to confirm and better characterize the PG episode(s) and underlying IBD. Clinical data collected included demographics (age, gender, ethnicity, race), family history, disease duration, disease phenotype (IBD subtype and disease location/behavior according to the Montreal Classification14), surgical history, treatment record, smoking status, and the presence or absence of other EIMs. IBD disease activity at the time of a PG episode was determined retrospectively by the presence of symptoms and, when available, elevated inflammatory markers, fecal calprotectin, and endoscopic correlation.
Case Definition An episode of PG was defined based on either dermatology consultant impression or a dermatologic lesion with three or more of the following typical clinical features15: (1) leg or peristomal location; (2) pathergy; (3) initial pustular lesion; (4) purulent discharge; (5) violaceous or undermined borders; (6) crater-like holes/cribriform scarring. 126
Histology reports were reviewed, when available, to exclude alternative diagnoses. Statistical Analysis Patient demographics and clinical characteristics were summarized using descriptive statistics. Ethical Considerations The study was approved by our Institutional Research Board (IRB), and all subjects provided written, informed consent when initially enrolled into the IRB-approved database.
Results Demographics We identified 104 patients from the database with at least one episode of PG. Among these, 24 did not meet our above criteria for defining PG, and it was determined that they did not have PG and were therefore excluded. Thus, 80 patients with a confirmed episode(s) of PG were included in this case series. At the time of the study, the database contained information on 4,137 patients, yielding an overall prevalence of PG among this tertiary care population of 1.9%. Table 1 outlines the demographic characteristics of the 80 patients with at least one episode of PG. Fifty-eight (73%) had CD, 19 (24%) had UC, and 3 had IBD-unclassified. Overall, 46 (58%) were female and 34 (42%) were male. Sixty-nine (86%) were of northern European origin. The mean age at IBD onset was 31 6 14.5 years. Twenty-four (30%) patients reported a positive family history of IBD. Thirty-one (39%) patients were former or current smokers at the time of IBD diagnosis. Fifty-three (66%) patients had experienced at least one other EIM. The majority of patients had previous exposure to corticosteroids (93%), 5aminosalicylic acid (5-ASA) or sulfasalazine (84%), immunomodulators (96%), or a biologic (85%). Colonic and ileocolonic disease were most common among those with CD (43% and 45%, respectively), and extensive colitis was most common among those with UC (85%). Overall, 93% of patients with PG had some degree of colonic inflammation. PG Characteristics Dermatology consultation was obtained in 31 (39%) cases, with 21 (26%) patients undergoing biopsy of the lesion,
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Table 1. Clinical and Demographic Characteristics of the IBD-PG Cohort PG Subjects Clinical/Demographic Feature Female Male Crohn disease Ulcerative colitis IBD-unclassified Disease reclassification Mean age at IBD onset (yr) 6 SD Smoking history Family history of IBD Previous IBD-related surgery Previous medication use Corticosteroids 5-ASA Immunomodulator* Cyclosporine Biologic{ Other{ Other EIM Oral ulcers Ophthalmologic Arthritis Sacroiliitis/ankylosing spondylitis Erythema nodosum PSC
n (% of overall cohort) 46 (58) 34 (42) 58 (73) 19 (24) 3 (3) 21 (26) 31 6 14.5 31 (39) 24 (30) 51 (64) 74 67 77 16 68 3 53 12 12 24 3
(93) (84) (96) (20) (85) (4) (66) (15) (15) (30) (, 1)
11 (14) 1 (, 1)
5-ASA 5 5-aminosalicylic acid; EIM 5 extraintestinal manifestation; IBD 5 inflammatory bowel disease; PG 5 pyoderma gangrenosum; PSC 5 primary sclerosing cholangitis. * 6-Mercaptopurine, azathioprine, methotrexate. { Infliximab, adalimumab, certolizumab, natalizumab. { Others include thalidomide.
and the remaining cases being diagnosed clinically. The mean age at onset of the first episode of PG was 39.3 years. The majority of patients had only one episode of PG (61 [76%]). Twelve (15%) patients had two to three episodes, and 7 (9%) had more than three episodes. Underlying IBD was active at the time of the PG episode(s) in 52 (65%) patients. Four patients developed PG several years before the onset and diagnosis of IBD. The location of the PG was variable (Table 2), with the most common sites being the lower extremity (53% with unilateral leg inflammation and 19% with bilateral leg inflammation). Peristomal PG was noted in 23% (18) of patients. Less common sites included the trunk, upper extremity, face (Figure 1), scalp, and perianal or pubic region (Figure 2).
Table 2. Features of Pyoderma Gangrenosum PG Subjects PG Feature
n (% of PG cohort)
Age at first PG episode IBD active at onset Number of PG episodes 1 2–3 .3 Location* Unilateral lower extremity Bilateral lower extremity Peristomal area Trunk Back Upper extremity Face Perianal area Pubic area Scalp
39.8 52 (65) 61 (76) 12 (15) 7 (9) 42 15 18 5 4 5 3 1 1 1
(53) (19) (23) (6) (5) (6) (4) (1) (1) (1)
IBD 5 inflammatory bowel disease; PG 5 pyoderma gangrenosum. * Patient may have had PG at more than one site.
Therapy A variety of therapeutic approaches were used for treating PG in this cohort. Most patients (71.3%) required multiple therapies to achieve PG healing, whereas the remaining patients were managed with a single agent. Six (8%) patients received no treatment. Thirty-one (39%) patients
Figure 1. Severe facial pyoderma gangrenosum. Note full-thickness ulceration with visualization of underlying dentition and characteristic ‘‘heaped-up’’ edges with a violaceous border. This lesion healed with a combination of cyclosporine, intravenous immunoglobulin, and hyperbaric oxygen treatments.
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Figure 2. Perianal pyoderma gangrenosum in a patient with ileal pouch-anal anastomosis. These lesions healed with intravenous corticosteroids and cyclosporine.
required hospitalization for a PG episode. At the time of PG onset, 10 (13%) were actively on an anti-TNF agent for the treatment of their underlying IBD. Systemic corticosteroids were the most commonly prescribed therapy, with 47 (59%) patients receiving either oral or intravenous steroids at some point during the PG episode. Intralesional injection of corticosteroids was used in 9 (11%) patients. Anti-TNF agents and cyclosporine were used in the treatment of PG with equal frequency (29%). Azathioprine was used as an adjuvant treatment in 6 (8%) patients. Hyperbaric oxygen was used in 3 (4%) patients, and intravenous immunoglobulin was used in 1 patient. Surgical intervention was part of the management of 16 (20%) patients. This included skin grafting, tissue de´bridement, and/or resiting of stoma. Four (5%) patients were managed exclusively with surgical intervention and did not receive any specific medical therapy for PG.
Discussion PG is a severe EIM of IBD, with lesions having significant pain and scarring and patients often requiring hospitalization. Moreover, PG management often requires aggressive immunosuppressant therapy, even in the absence of active underlying IBD. The current study aimed to characterize the clinical and dermatologic features of a large IBD patient cohort followed at a tertiary referral center with at least one episode of PG. We noted 80 cases of PG among the cohort, yielding a prevalence of 1.9%. This is in agreement with other published series in which the prevalence of PG has ranged 128
from 0.5 to 5%.8–11,16 Among our cases, 73% had CD, although previous studies have not consistently demonstrated a clear association between a particular IBD subtype with PG. PG was more commonly found in patients with UC in a large population-based Swiss cohort,16 whereas in a population-based cohort from Manitoba, PG was more prevalent in CD,10 and this finding has subsequently been supported by others.17 Our results may be, in part, a reflection of a higher incidence of CD in the patients seen at our center, and it is important to note that this cohort is a tertiary referral center–ascertained cohort, in contrast to the Swiss and Manitoba-based studies above. Although data on IBD subtype are conflicting, there is more consistency among studies evaluating IBD disease location and association with PG. Colonic disease has previously been associated with several EIMs, including PG, erythema nodosum, and IBD-associated arthritis.7–18 We similarly noted that colonic and ileocolonic disease was most common among those with CD (43% and 45%, respectively), and extensive colitis was most common among those with UC (85%). Overall, 93% of patients had some degree of colonic inflammation. The predominance of colonic disease in subjects with EIM suggests underlying mechanisms intrinsic to colonic inflammation, which may include genetic, immunologic, and/or microbiologic interactions such as cross-reactivity of skin, joint, and eye and gut antigens.19 This intriguing overlap and potential link are further supported by the association between perinuclear antineutrophil cytoplasmic antibodies (pANCAs), a serologic marker often detected in patients with colonic IBD, including UC and UC-like CD phenotypes,20 with a number of EIMs, such as uveitis.21 In addition genetic variation at the major histocompatibility complex has previously been associated with both extensive colonic disease and the presence of EIMs.22 We noted a slight female predominance (58%) among our PG cohort. Several studies have previously noted an association between EIMs and female gender, including a Swedish study that found that erythema nodosum was more than three times more likely to occur in women.18 In addition, Vavricka and colleagues noted an EIM prevalence of 50% in females compared to only 34% in males (p , .001).16 A female predilection for PG is less clear from the literature. A recent systematic review identified 60 cases of PG, 55% of whom were female.7 The findings of female predominance suggest a possible role of hormonal influences, and some have suggested that estrogen may have a modulating effect on EIMs.23 Clearly, more study is needed to explain these observed gender differences. The literature suggests that patients with one EIM are more likely to develop additional EIMs.16–18 For example,
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Vavricka and colleagues observed that patients with IBDassociated arthritis had an odds ratio of 2.9 for subsequent PG development.16 We noted that two-thirds of patients with PG had either a previous history of EIM or subsequently developed another EIM. IBD-associated arthritis was the most common other EIM noted in our cohort. These findings point to a common underlying pathophysiology for EIMs in IBD, suggesting a need for further study to better define the apparent common etiology in CD. We noted a mean age at first episode of PG onset of 39 years. This age is somewhat younger compared to other series, in which the age of PG diagnosis ranged from 45 to 62 years.23–27 However, these published cases were not necessarily limited to patients with IBD and so included patients with PG associated with hematologic disorders, for example, which are more commonly seen in older individuals. An IBD-specific cohort found an age at PG onset of 36 years, similar to our results.17 The relationship between PG onset or recurrence and underlying IBD disease activity is unclear. Traditionally, PG behavior and IBD disease activity were thought to follow independent courses, with approximately half of patients having active disease at the time of PG onset.6 A more recent study noted that 75% of patients with PG onset had active disease.28 We found that approximately two-thirds of patients had active IBD at the time of PG onset. These findings suggest that the association between disease activity and PG is stronger than previously reported. More prospective studies objectively evaluating disease activity at the time of PG development are needed to better characterize the influence of active intestinal inflammation on PG, as has been shown with other EIMs, such as erythema nodosum.28 Although PG location was variable, the leg was the most common site, with 57 episodes of PG involving the lower extremity either unilaterally or bilaterally. The propensity for the lesion to form on the lower extremity is consistent with most other reports evaluating PG characteristics.1,5–7,15 Pathergy, the development or worsening of a lesion after trauma, is a classic characteristic of PG and may be responsible for the high incidence of lesions on the leg as this is a high-risk area for minor injuries.15 This phenomenon may also explain the finding of peristomal pyoderma as minor trauma to the area with appliance changes is common. We noted 15 episodes of peristomal pyoderma, making it the second most common site for PG development, similar to previous reports.15,17,25 Several patients had multiple concurrent lesions, and although most had only one episode of PG, nearly one-quarter of patients had multiple episodes over time. Some have
recommended a more aggressive management approach for patients with multilesional PG, citing a greater tendency for lesions to progress when present in more than one location.29 A number of less commonly encountered sites were also observed, including the face (see Figure 1) and perianal area (see Figure 2). Whether multifocal PG or the occurrence of a lesion on an atypical site carries a worse prognosis needs to be further elucidated. A variety of therapies were used in the management of PG among our cohort. The finding that over 70% of patients required multiple treatments to achieve PG healing and that approximately 40% of patients required hospital admission specifically for the management of PG underscores the severe nature of many of these PG episodes. Systemic corticosteroids were the most commonly used treatment, with nearly 60% of patients receiving intravenous or oral corticosteroids. Only 11% were treated with topical or intralesional steroids, a lower figure than most other reports,26,27 suggesting that cases among our cohort were considered too severe for local therapy. Although no controlled studies for corticosteroids are available, many reports have shown their efficacy, and they are therefore considered by many to be first-line therapy for PG.29–31 A notable exception was a report by Vidal and colleagues, in which cyclosporine was more commonly used and more effective than corticosteroids, leading the authors to conclude that cyclosporine should be first-line treatment for the induction of rapid wound healing.27 Four percent of patients received hyperbaric oxygen for treatment, usually as an adjuvant therapy for severe cases. Just under one-third of our cohort received intravenous cyclosporine, usually together with systemic steroids. Most of these patients started cyclosporine after failing to improve after several days of intravenous steroids. This practice is supported by a small prospective cohort of 11 patients who were treated with cyclosporine after failing steroid monotherapy, whereby 100% achieved complete wound healing, with a mean time to healing of 1.4 months.12 Moreover, the authors noted that patients transitioned to azathioprine had no recurrence, a practice that was uncommon in our cohort, with only six patients started on azathioprine as PG therapy. Twenty-nine percent of patients were started on anti-TNF therapy in the management of PG. As with patients started on cyclosporine, these patients were largely steroid monotherapy failures. Interestingly, 13% of patients were already on anti-TNF therapy at the time of PG onset. This may suggest a unique mechanism of PG development in this subset of patients
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given that anti-TNF has been demonstrated to heal PG in a small randomized controlled trial and a number of small case series.13–32 A similar parallel has been noted with psoriasis, a dermatologic lesion also treated with anti-TNF therapy. Lesions erupting paradoxically following anti-TNF therapy have been described in a subset of IBD patients.33,34 Uncontrolled interferon-a levels in the setting of TNF inhibition are one hypothesis for a mechanism underlying this paradoxical finding.35 More studies on the underlying pathophysiology and immunologic underpinnings of PG are needed to better clarify optimal treatment regimen(s). A number of limitations in the current study are noted. First, the retrospective nature of this study limited the ability to collect standardized information. The quality of the description of PG lesions and associated therapy was variable, a well-recognized shortcoming of retrospective reviews of this relatively rare condition. Important treatment details, including efficacy and time to healing, were not consistently documented and were therefore not reported. A standardized approach for monitoring the clinical course of PG is therefore needed. Moreover, assessing IBD disease activity retrospectively relies on objective assessments available in the medical record at that time (eg, endoscopic reports, fecal calprotectin, inflammatory markers). Assessment of disease activity was not always formally assessed at the time of new PG diagnosis. Second, our case definition was limited by the fact that no validated definition of PG is available. However, we used the descriptive, clinical criteria cited by most authors; therefore, our definition is well aligned with other reports in the literature. Third, our cohort consisted of severe cases of PG followed at a tertiary IBD referral center and therefore likely reflects more severe cases and limits the generalizability of our findings to other settings. However, despite these limitations, we describe one of the largest case series of PG in a well-characterized cohort of patients with IBD. Hospitalization was not uncommon, underscoring the morbidity and cost associated with this severe EIM. Moreover, a variety of treatment strategies were used, highlighting the lack of clear guidelines as to how to effectively manage this complex group of patients. More study on the clinical characteristics of PG complicating IBD is needed, as well as on the underlying genetic and immunologic underpinnings of this debilitating dermatologic manifestation.
Acknowledgments Financial disclosure of authors: Gil Y. Melmed, MD acts as a consultant for AbbVie, Jannsen, UCB, Celgene, Given 130
Imaging, Luitpold Pharmaceuticals. He also received grant support from Prometheus labs and Pfizer. Financial disclosure of reviewers: None reported.
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