HHS Public Access Author manuscript Author Manuscript
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01. Published in final edited form as: J Cutan Med Surg. 2014 October ; 18(5): 361.
Pyoderma gangrenosum among patients with inflammatory bowel disease: a descriptive cohort study Adam V. Weizman, MSc, MD1,2, Brian Huang, MD1, Stephan Targan, MD1, Marla Dubinsky, MD3, Phillip Fleshner, MD1, Manreet Kaur, MD1, Andrew Ippoliti, MD1, Deepa Panikkath1, Eric Vasiliauskas, MD1, David Shih, MD, PhD1, Dermot P.B. McGovern, MD, PhD1,4, and Gil Y. Melmed, MD, MPH1
Author Manuscript
1F.
Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
2Women’s
College Hospital, Division of Gastroenterology, University of Toronto, Toronto, Ontario,
Canada 3Department
of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, California
4Medical
Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, California
Abstract Author Manuscript
BACKGROUND—Pyoderma gangrenosum (PG) is a severe extra-intestinal 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—80 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 involvement. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing.
Author Manuscript
CONCLUSIONS—We have described 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. Keywords Crohn’s disease; dermatology; extra-intestinal manifestations; inflammatory bowel disease; inflammatory dermatoses; pyoderma gangrenosum; ulcerative colitis
Correspondence: Gil Y. Melmed, M.D., 8730 West Alden Dr. Thalians 2E, Los Angeles, California, 90048, [email protected].
Weizman et al.
Page 2
Author Manuscript
INTRODUCTION Pyoderma gangrenosum (PG), a neutrophilic dermatosis affecting the skin, is one of the more common extra-intestinal manifestations 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 border5 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 (e.g. adjacent to stoma) 6,7.
Author Manuscript
PG occurs in 0.5–5% of patients with IBD and has previously been shown to be more common in women, IBD patients with other extra-intestinal manifestations and has also been particularly associated with ulcerative colitis (UC) and among patients with colonic Crohn’s disease (CD)7–11. The development of PG is one of the more severe extra-intestinal manifestations of IBD with the potential for both significant morbidity and tremendous impact on activities of daily living and quality of life5–6. Severe disease can be cosmetically disfiguring and may lead to permanent scarring, significant pain, bacterial super-infection, 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 activity7,12,13. 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 Author Manuscript
Subjects
Author Manuscript
Subjects with PG were identified using our longitudinal IBD database, which contains detailed clinical (demographics, disease phenotype, disease history, extra-intestinal manifestations, treatment record), serologic, and genetic data on over 4000 patients with IBD. Medical records of patients identified as having one or more episodes of PG between the years 1997–2012 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 presence or absence of other extra-intestinal manifestations. 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: (i) leg or peristomal location (ii) pathergy (iii) initial pustular lesion (iv) purulent discharge (v)
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01.
Weizman et al.
Page 3
Author Manuscript
violacious or undermined borders (vi) crater-like holes/cribiform scarring. 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, and all subjects provided written, informed consent when initially enrolled into the IRB-approved database.
RESULTS Author Manuscript
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 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 4137 patients, yielding an overall prevalence of PG among this tertiary care population of 1.9%.
Author Manuscript
Table 1 outlines the demographic characteristics of the 80 patients with at least one episode of PG. Fifty-eight (73%) had Crohn’s disease, 19 (24%) had ulcerative colitis, 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 of IBD onset was 31 + 14.5 years. Twenty-four (30%) patients reported a positive family history of IBD. Thirty-one patients (39%) were former or current smokers at the time of IBD diagnosis. Fifty-three (66%) had experienced at least one other extra-intestinal manifestation. The majority of patients had previous exposure to corticosteroids (93%), 5ASA or sulfasalazine (84%), immunomodulators (96%), or a biologic (85%). Colonic and ileocolonic disease were most common among those with Crohn’s disease (43% and 45%, respectively) and extensive colitis was most common among those with ulcerative colitis (85%). Overall, 93% of patients with PG had some degree of colonic involvement. Pyoderma Characteristics
Author Manuscript
Dermatology consultation was obtained in 31 (39%) of cases with 21 (26%) patients undergoing biopsy of the lesion, and the remaining cases diagnosed clinically. The mean age of onset of the first episode PG was 39.3 years. The majority of patients had only one episode of PG (61 [76%]). Twelve (15%) patients had 2–3 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.
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01.
Weizman et al.
Page 4
Author Manuscript
PG location was variable (Table 2) with the most common sites being the lower extremity (53% with unilateral leg involvement and 19% bilateral leg involvement). Peri-stomal PG was noted in 23% (18) of patients. Less common sites included trunk, upper extremity, face (figure 1), scalp, and perianal/pubic region (figure 2). 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, while the remaining patients were managed with a single agent. Six patients (8%) received no treatment. Thirty-one (39%) patients 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.
Author Manuscript
Systemic corticosteroids was the most commonly prescribed therapy, with 47 (59%) of patients receiving either oral or intravenous steroids at some point during the PG episode. Intra-lesional injection of corticosteroids were used in 9 (11%) of 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 one patient. Surgical intervention was part of the management of 16 (20%) patients. This included skin grafting, tissue debridement, and/or re-siting of stoma. Four (5%) patients were managed exclusively with surgical intervention and did not receive any specific medical therapy for PG.
DISCUSSION
Author Manuscript
Pyoderma gangrenosum is a severe extra-intestinal manifestation 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 clinical and dermatologic features of a large IBD patient cohort followed at a tertiary, referral center with at least one episode of PG.
Author Manuscript
We noted 80 cases of PG among the cohort yielding a prevalence of 1.9%. This is agreement with other published series in which prevalence of PG has ranged from 0.5–5%8–11,16. Among our cases, 73% had Crohn’s disease 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 cohort16, whereas in a population-based cohort from Manitoba, PG was more prevalent in CD10 and this finding subsequently been supported by others17. Our results may be, in part, a reflection of a higher incidence of CD in the patients seen at our center and its important to note that this cohort is a tertiary referral center ascertained cohort in contrast to the Swiss and Manitoba-based studies above. While data on IBD subtype is conflicting, there is more consistency among studies evaluating IBD disease location and association with PG. Colonic disease has previously been associated with a several EIM’s including PG, erythema nodosum, and IBD-associated arthritis7–16–18. We similarly noted that colonic and ileocolonic disease was most common among those with Crohn’s disease (43% and 45%, respectively) and extensive colitis was most common among those with ulcerative colitis (85%). Overall, 93% of
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01.
Weizman et al.
Page 5
Author Manuscript
patients had some degree of colonic involvement. 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 crossreactivity of skin, joint, and eye and gut antigens19. This intriguing overlap and potential link is further supported by the association between perinuclear (p) antineutrophil cytoplasmic antibodies (ANCAs), a serologic marker often detected in patients with colonic IBD including UC and UC-like CD phenotypes20, with a number of EIM such as uveitis21. In addition genetic variation at the MHC has previously been associated with both extensive colonic disease and the presence of EIMs22.
Author Manuscript
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 3 times more likely to occur in women18. In addition, Vavricka et al. noted an EIM prevalence of 50% in females compared to only 34% in males (p
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01. Published in final edited form as: J Cutan Med Surg. 2014 October ; 18(5): 361.
Pyoderma gangrenosum among patients with inflammatory bowel disease: a descriptive cohort study Adam V. Weizman, MSc, MD1,2, Brian Huang, MD1, Stephan Targan, MD1, Marla Dubinsky, MD3, Phillip Fleshner, MD1, Manreet Kaur, MD1, Andrew Ippoliti, MD1, Deepa Panikkath1, Eric Vasiliauskas, MD1, David Shih, MD, PhD1, Dermot P.B. McGovern, MD, PhD1,4, and Gil Y. Melmed, MD, MPH1
Author Manuscript
1F.
Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
2Women’s
College Hospital, Division of Gastroenterology, University of Toronto, Toronto, Ontario,
Canada 3Department
of Pediatrics, Pediatric Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, California
4Medical
Genetics Research Institute, Cedars-Sinai Medical AU2 Center, Los Angeles, California
Abstract Author Manuscript
BACKGROUND—Pyoderma gangrenosum (PG) is a severe extra-intestinal 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—80 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 involvement. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing.
Author Manuscript
CONCLUSIONS—We have described 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. Keywords Crohn’s disease; dermatology; extra-intestinal manifestations; inflammatory bowel disease; inflammatory dermatoses; pyoderma gangrenosum; ulcerative colitis
Correspondence: Gil Y. Melmed, M.D., 8730 West Alden Dr. Thalians 2E, Los Angeles, California, 90048, [email protected].
Weizman et al.
Page 2
Author Manuscript
INTRODUCTION Pyoderma gangrenosum (PG), a neutrophilic dermatosis affecting the skin, is one of the more common extra-intestinal manifestations 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 border5 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 (e.g. adjacent to stoma) 6,7.
Author Manuscript
PG occurs in 0.5–5% of patients with IBD and has previously been shown to be more common in women, IBD patients with other extra-intestinal manifestations and has also been particularly associated with ulcerative colitis (UC) and among patients with colonic Crohn’s disease (CD)7–11. The development of PG is one of the more severe extra-intestinal manifestations of IBD with the potential for both significant morbidity and tremendous impact on activities of daily living and quality of life5–6. Severe disease can be cosmetically disfiguring and may lead to permanent scarring, significant pain, bacterial super-infection, 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 activity7,12,13. 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 Author Manuscript
Subjects
Author Manuscript
Subjects with PG were identified using our longitudinal IBD database, which contains detailed clinical (demographics, disease phenotype, disease history, extra-intestinal manifestations, treatment record), serologic, and genetic data on over 4000 patients with IBD. Medical records of patients identified as having one or more episodes of PG between the years 1997–2012 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 presence or absence of other extra-intestinal manifestations. 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: (i) leg or peristomal location (ii) pathergy (iii) initial pustular lesion (iv) purulent discharge (v)
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01.
Weizman et al.
Page 3
Author Manuscript
violacious or undermined borders (vi) crater-like holes/cribiform scarring. 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, and all subjects provided written, informed consent when initially enrolled into the IRB-approved database.
RESULTS Author Manuscript
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 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 4137 patients, yielding an overall prevalence of PG among this tertiary care population of 1.9%.
Author Manuscript
Table 1 outlines the demographic characteristics of the 80 patients with at least one episode of PG. Fifty-eight (73%) had Crohn’s disease, 19 (24%) had ulcerative colitis, 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 of IBD onset was 31 + 14.5 years. Twenty-four (30%) patients reported a positive family history of IBD. Thirty-one patients (39%) were former or current smokers at the time of IBD diagnosis. Fifty-three (66%) had experienced at least one other extra-intestinal manifestation. The majority of patients had previous exposure to corticosteroids (93%), 5ASA or sulfasalazine (84%), immunomodulators (96%), or a biologic (85%). Colonic and ileocolonic disease were most common among those with Crohn’s disease (43% and 45%, respectively) and extensive colitis was most common among those with ulcerative colitis (85%). Overall, 93% of patients with PG had some degree of colonic involvement. Pyoderma Characteristics
Author Manuscript
Dermatology consultation was obtained in 31 (39%) of cases with 21 (26%) patients undergoing biopsy of the lesion, and the remaining cases diagnosed clinically. The mean age of onset of the first episode PG was 39.3 years. The majority of patients had only one episode of PG (61 [76%]). Twelve (15%) patients had 2–3 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.
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01.
Weizman et al.
Page 4
Author Manuscript
PG location was variable (Table 2) with the most common sites being the lower extremity (53% with unilateral leg involvement and 19% bilateral leg involvement). Peri-stomal PG was noted in 23% (18) of patients. Less common sites included trunk, upper extremity, face (figure 1), scalp, and perianal/pubic region (figure 2). 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, while the remaining patients were managed with a single agent. Six patients (8%) received no treatment. Thirty-one (39%) patients 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.
Author Manuscript
Systemic corticosteroids was the most commonly prescribed therapy, with 47 (59%) of patients receiving either oral or intravenous steroids at some point during the PG episode. Intra-lesional injection of corticosteroids were used in 9 (11%) of 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 one patient. Surgical intervention was part of the management of 16 (20%) patients. This included skin grafting, tissue debridement, and/or re-siting of stoma. Four (5%) patients were managed exclusively with surgical intervention and did not receive any specific medical therapy for PG.
DISCUSSION
Author Manuscript
Pyoderma gangrenosum is a severe extra-intestinal manifestation 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 clinical and dermatologic features of a large IBD patient cohort followed at a tertiary, referral center with at least one episode of PG.
Author Manuscript
We noted 80 cases of PG among the cohort yielding a prevalence of 1.9%. This is agreement with other published series in which prevalence of PG has ranged from 0.5–5%8–11,16. Among our cases, 73% had Crohn’s disease 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 cohort16, whereas in a population-based cohort from Manitoba, PG was more prevalent in CD10 and this finding subsequently been supported by others17. Our results may be, in part, a reflection of a higher incidence of CD in the patients seen at our center and its important to note that this cohort is a tertiary referral center ascertained cohort in contrast to the Swiss and Manitoba-based studies above. While data on IBD subtype is conflicting, there is more consistency among studies evaluating IBD disease location and association with PG. Colonic disease has previously been associated with a several EIM’s including PG, erythema nodosum, and IBD-associated arthritis7–16–18. We similarly noted that colonic and ileocolonic disease was most common among those with Crohn’s disease (43% and 45%, respectively) and extensive colitis was most common among those with ulcerative colitis (85%). Overall, 93% of
J Cutan Med Surg. Author manuscript; available in PMC 2016 November 01.
Weizman et al.
Page 5
Author Manuscript
patients had some degree of colonic involvement. 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 crossreactivity of skin, joint, and eye and gut antigens19. This intriguing overlap and potential link is further supported by the association between perinuclear (p) antineutrophil cytoplasmic antibodies (ANCAs), a serologic marker often detected in patients with colonic IBD including UC and UC-like CD phenotypes20, with a number of EIM such as uveitis21. In addition genetic variation at the MHC has previously been associated with both extensive colonic disease and the presence of EIMs22.
Author Manuscript
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 3 times more likely to occur in women18. In addition, Vavricka et al. noted an EIM prevalence of 50% in females compared to only 34% in males (p
