The Inpatient Burden and Comorbidities of Pyoderma Gangrenosum in Adults in the United States

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7-3-2020

The inpatient burden and comorbidities of pyoderma gangrenosum in adults in the United States

Shanthi Narla Henry Ford Health System, [email protected]

Jonathan I. Silverberg

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Recommended Citation Narla S, and Silverberg JI. The inpatient burden and comorbidities of pyoderma gangrenosum in adults in the United States. Arch Dermatol Res 2020.

This Article is brought to you for free and open access by the Dermatology at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Dermatology Articles by an authorized administrator of Henry Ford Health System Scholarly Commons. Archives of Dermatological Research https://doi.org/10.1007/s00403-020-02098-7

ORIGINAL PAPER

The inpatient burden and comorbidities of pyoderma gangrenosum in adults in the United States

Shanthi Narla1 · Jonathan I. Silverberg2

Received: 24 April 2020 / Accepted: 17 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract Hospital admission is often necessary for management of pyoderma gangrenosum (PG), including wound care and pain control. No large-scale controlled studies examined the burden of hospitalization for PG. The objective of this study is to determine the prevalence, predictors, outcomes, and costs of hospitalization for PG in United States adults. Data were analyzed from the 2002 to 2012 National Inpatient Sample, including a 20% representative sample of United States hospitalizations. The prevalence of hospitalization for PG increased between 2002 and 2012. Primary admission for PG was associated with age 40–59 years, female sex, black race/ethnicity, second-quartile household income, public or no insurance, and multiple chronic conditions. PG admissions were more likely at teaching and medium or large hospitals. Geometric-mean length and cost of hospitalization were higher in inpatients with vs. without a primary diagnosis of PG. The majority of inpatients with PG were classifed with minor (64.4%) or moderate (25.7%) likelihood of dying, but moderate (52.5%) and major (28.7%) loss of function. PG was associated with numerous other health disorders. The limitation of this study is the lack of data on PG treatment. This study demonstrated a substantial and increasing inpatient burden of PG in the United States, with considerable disability and mortality risk, multiple comorbid health disorders, and costs.

Keywords Pyoderma gangrenosum · Inpatient · Comorbidities · Cost · Hospital · Mortality

Abbreviations CCI Charlson comorbidity index ICD-9-CM International Classifcation of Disease 9th HCUP Healthcare cost and utilization project edition Clinical Modifcation AHRQ Agency for healthcare research and quality IBD Infammatory bowel disease LOS Length of stay PG Pyoderma gangrenosum APRDRG All Patient Refned Diagnosis-Related Group AIDS Acquired immunodefciency syndrome PUD Peptic ulcer disease DM Diabetes mellitus Introduction HS Hidradenitis suppurativa NIS Nationwide inpatient sample Pyoderma gangrenosum (PG) is a chronic, heterogeneous, CI Confdence interval infammatory skin disease characterized by aseptic neutrophilic infltration and systemic infammation. The most com- mon variant of PG is the ulcerative subtype, which typically Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00403-020-02098-7) contains presents as painful and pruritic erythematous lesions that supplementary material, which is available to authorized users. rapidly progress to blistered or necrotic ulcers most often on the lower extremities [1]. Wound care, anti-infammatory * Jonathan I. Silverberg treatments, and pain control are mainstays of treatment. Hos- [email protected] pitalization may be necessary for evaluation and manage- 1 Department of Dermatology, Henry Ford Hospital, Detroit, ment of rapidly progressive PG and less commonly chronic MI 48202, USA refractory disease. 2 Department of Dermatology, The George Washington The long-term outcome of PG remains poor with University School of Medicine and Health Sciences, Suite relapses occurring in up to 70% of cases and mortality rates 2B‑430, 2150 Pennsylvania Avenue, Washington, DC 20037, as high as 30% [2]. A case series of 26 patients requiring USA

Vol.:(0123456789)1 3 Archives of Dermatological Research hospitalization for PG was performed at an Australian ter- during hospitalization, including ventilation (overall, < 96 tiary teaching hospital. The median length of stay in the hos- or > 96 h), physical therapy, and diagnostic procedures on pital was 17 days (range 1–90 days), with 16 having multiple skin and subcutaneous tissue including skin biopsies, skin admissions. Investigations and treatments included c-reac- debridement, and skin grafting. Mortality risk and functional tive protein, wound cultures, dressings, topical treatments, severity were classifed according to the All Patient Refned and systemic immunosuppressive therapy [3]. A previous Diagnosis-Related Group (APRDRG) coded in NIS based on study of US inpatients compared the clinical characteristics software developed by the 3M Health Information Services of those hospitalized for PG with vs. without infammatory (2008). APRDRG incorporates severity of illness subclasses bowel disease (IBD); however, general associations and and is used to relate the type of patients treated to the costs trends in hospitalization for PG were not directly examined incurred by the hospital. Discharge status was assessed. [4]. A few large-scale studies examined the overall inpatient burden of PG, especially in the United States. Furthermore, Statistical analysis prior studies examined a limited set of PG comorbidities [5]. Despite the signifcant morbidity and risk of mortality, Data analyses were performed using SAS version 9.4 (SAS no large-scale controlled studies examined the multitude of Institute, Cary, NC). Weighted prevalence (95% CI) of hos- comorbidities of PG that have been reported in the literature, pitalization with a primary ICD-CM code of PG among including rarer disorders identifed in case reports and case inpatients was determined. Hospital cost for inpatient care series. This study sought to determine the prevalence, length was calculated based on the total charge of hospitalization of stay (LOS), and cost of care for hospitalization for PG and and the cost-to-charge ratio estimated by the Healthcare Cost medical comorbidities of PG in United States adults. and Utilization Project. Costs were adjusted for infation to the year 2014 according to the Consumer Price Index (US Bureau of Labor Statistics, 2015). Summary statistics were Methods generated for LOS, infation-adjusted cost of care, including sum, geometric mean, and 95% CI for hospitalizations The 2002–2012 National Inpatient Sample (NIS) was ana- with a primary or no diagnosis of PG. All statistical models lyzed. The NIS was developed as part of the Healthcare Cost employed SURVEY procedures, including discharge trend and Utilization Project (HCUP) sponsored by the Agency weights, sample strata accounting for hospital’s census for Healthcare Research and Quality (AHRQ). Each year region or division, ownership/control, location/teaching and of the NIS contains an approximately 20% stratifed repre- number of beds that were provided by NIS, and clustering by sentative sample of all US hospitalizations. All data were individual hospital. These models allow for representative de-identifed. No attempts were made to identify any indi- weighted estimates of frequency and prevalence of hospital viduals in the database. Patient consent was not obtained as discharges across the United States. the databases were received de-identifed. All parties were Survey logistic regression models were used to determine compliant to HCUP’s formal data use agreement. The study the associations of hospitalization for PG. The dependent was approved by the institutional review board at North- variable was hospitalization with vs. without a primary western University. diagnosis of PG. The independent variables included age, The databases were searched for a primary discharge sex, race/ethnicity, health insurance, number of chronic diagnosis of PG using the International Classifcation of Dis- conditions, hospital location, teaching status of hospital, eases, Ninth Revision, Clinical Modifcation (ICD-9-CM) admission month/season, hospital region, median house- code 686.01 (Supplemental Table 1). A previous study hold income national quartile for patient ZIP Code, and validated the use of the ICD-9-CM code 686.01 in hospi- hospital bed size. Chronic conditions were determined tal databases to identify PG [6]. The NIS defned primary using the HCUP chronic condition indicator for conditions diagnosis as the medical condition principally responsible lasting ≥ 12 months and meeting one or both of the follow- for the hospitalization of the patient and was assigned at ing: places limitations on self-care, independent living, and the time of hospital discharge. The control group included social interactions and/or results in the need for ongoing all hospitalizations without any PG and excluded normal intervention with medical products, services, and special pregnancy/delivery, yielding a representative cohort of US equipment. Crude odds ratios (ORs) and 95% CIs were esti- hospitalizations. mated. Multivariate regression models were constructed Associated comorbidities of PG were identifed using using stepwise selection (α = 0.10) from the previously ICD-9-CM or clinical classifcation codes. The comorbidi- mentioned covariates to determine associations of hospi- ties included in the analyses were identifed based on prior talization. Adjusted OR (aOR) and 95% CI were estimated. retrospective analyses and case reports [7]. ICD-9-CM Survey logistic regression models were also used to procedure codes were used to identify procedures done determine the associations of a primary or secondary

1 3 Archives of Dermatological Research diagnosis of PG with comorbid health disorders. Mul- Associations of hospitalization for PG tivariable models included age (continuous), sex (male, female), race (white, nonwhite), and insurance status (yes, Adults with a primary diagnosis of PG were signifcantly no) as covariables. Crude and adjusted OR and 95% CIs younger than those without a primary diagnosis of PG were estimated. (mean [95% CI] 53.0 [52.1–53.9] vs. 61.0 [60.8–61.2] Post hoc correction for multiple dependent tests was years; P = 0.0002). Adults who were admitted for PG were performed by minimizing the false discovery rate [8]. more likely to be age 40–59 years, females, have black race/ Two-sided corrected P values are presented and consid- ethnicity, Medicaid insurance, and 2–5 chronic conditions, ered significant if ≤ 0.05. but were less likely to have Asian or other/multiracial race/ ethnicity, or Medicare insurance (Table 1). There were no associations between hospitalization for PG and median household income. Results In multivariable logistic regression models invoking stepwise selection, primary admission for PG in adults was Hospitalization prevalence and trends associated with ages 40–59 years old, female sex, black race/ ethnicity, second quartile for household income, public or Overall, there were 63,229,041 hospitalizations cap- no insurance, having multiple chronic conditions, and being tured in the NIS between 2002 and 2012, including 1907 admitted to a teaching hospital and a hospital with medium (weighted frequency: 9075) primary hospital admissions or large bed size (Table 1). for PG in adults and 5662 (weighted frequency: 27,063) secondary hospital admissions for PG in adults. The Cost of care prevalence of hospitalization ranged from 31 to 39 per million hospitalized adults (Fig. 1). The prevalence of The mean total infation-adjusted cost of care for hospitaliza- hospitalization for PG increased between 2002 and 2012 tion with a primary diagnosis of PG was $9,766,542 per year (P = 0.0374). in adults. The geometric-mean [95% CI] cost of hospitali- Adults were more likely to be admitted for PG to teach- zation was signifcantly higher in adults with vs. without a ing hospitals, in metropolitan areas and the South, and in primary diagnosis of PG ($8111 [$7728–$8513] vs. $7622 large-sized hospitals (Table 1). [$7540–$7704], P = 0.0184).

Fig. 1 The prevalence of hospi- 45 talization per million hospitalized adults for a primary diag- 39 nosis of pyoderma gangrenosum 40 during the years 2002–2003,

2004–2005, 2006–2007, 2008– s 35 2009, 2010–2011, and 2012. 32 31 Missing data were encountered 30 in 370,476 (0.1%) for sex, 30 28 60,959,081 (20.2%) for race/ ethnicity, 33,471,149 (11.1%) 26 for income quartile, 611,731 25 (0.2%) for insurance status, 0 (0.0%) for age, 44,978,381 (14.9%) for hospital locale, 0 20 (0.0%) for number of chronic conditions, 1,277,750 (0.4%) for bed size of hospital, 0 (0.0%) 15 for hospital region, 25,055,337 (8.3%) for admission month/ alence per million inpatient season, and 28,297,603 (9.3%) 10 for teaching status Prev

0 2002-20032004-2005 2006-20072008-2009 2010-20112012

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Table 1 Associations of hospitalization with a primary diagnosis of pyoderma gangrenosum in adults Variable Primary inpatient diagnosis of PG No Yes Wtd freq % Prev [95% CI] Wtd freq % Prev [95% CI] Crude OR [95% CI] P Adj OR [95% CI] P

Age (yr) 18–39 46,278,257 15.4 [15.1–15.6] 1747 19.3 [16.7–21.8] 1.00 [REF] – 1.00 [REF] – 40–59 88,083,207 29.2 [29.0–29.5] 4409 48.6 [45.8–51.4] 1.33 [1.12–1.57] 0.0021 1.33 [1.24–1.43] 0.0002 60–79 108,135,308 35.9 [35.7–36.1] 2339 25.8 [23.3–28.2] 0.57 [0.48–0.69] 0.0002 0.54 [0.49–0.59] 0.0002 80+ 58,721,756 19.5 [19.2–19.8] 579 6.4 [5.2–7.6] 0.26 [0.21–0.33] 0.0002 0.23 [0.20–0.26] 0.0002 Sex Male 135,555,779 45.1 [44.9–45.2] 3024 33.4 [30.6–36.1] 1.00 [REF] – 1.00 [REF] – Female 165,292,287 54.9 [54.8–55.1] 6036 66.6 [63.4–69.4] 1.64 [1.45–1.85] 0.0002 1.68 [1.59–1.78] 0.0002 Race/ethnicity White 171,976,159 71.6 [70.5–72.7] 5010 68.7 [65.1–72.2] 1.00 [REF] – 1.00 [REF] – Black 34,084,505 14.2 [13.4–14.9] 1509 20.7 [17.6–23.7] 1.52 [1.27–1.82] 0.0002 1.20 [1.12–1.29] 0.0002 Hispanic 21,711,349 9.0 [8.3–9.7] 574 7.9 [5.5–10.2] 0.91 [0.67–1.23] 0.6090 0.75 [0.68–0.83] 0.0002 Asian 4,611,488 1.9 [1.7–2.1] 76 1.0 [0.5–1.6] 0.57 [0.35–0.94] 0.0424 0.65 [0.52–0.80] 0.0023 Other 7,877,722 3.3 [3.0–3.6] 128 1.8 [1.1–2.4] 0.56 [0.38–0.82] 0.0051 0.38 [0.30–0.48] 0.0002 Annual household income—quartile 1st 78,402,992 29.3 [28.3–30.3] 2492 30.4 [27.3–33.4] 1.17 [0.98–1.40] 0.1142 1.09 [1.00–1.18] 0.1393 2nd 69,885,611 26.1 [25.4–26.8] 2224 27.1 [24.6–29.7] 1.17 [0.99–1.39] 0.0963 1.18 [1.09–1.28] 0.0011 3rd 63,362,925 23.7 [23.0–24.3] 1964 23.9 [21.2–26.7] 1.14 [0.96–1.37] 0.1934 1.08 [1.00–1.17] 0.1442 4th 56,096,723 21.0 [19.8–22.1] 1522 18.6 [16.2–20.9] 1.00 [REF] – 1.00 [REF] – Insurance Medicare 153,364,237 51.0 [50.5–51.5] 3544 39.2 [36.3–42.1] 0.69 [0.61–0.79] 0.0002 1.33 [1.23–1.43] 0.0002 Medicaid 32,792,526 10.9 [10.5–11.3] 1508 16.7 [14.2–19.2] 1.37 [1.14–1.65] 0.0015 1.26 [1.16–1.37] 0.0002 Private insurance 86,272,125 28.7 [28.2–29.2] 2889 32.0 [29.4–34.6] 1.00 [REF] – 1.00 [REF] – No insurance 28,177,951 9.4 [9.0–9.8] 1091 12.1 [10.2–14.0] 1.16 [0.97–1.39] 0.1579 1.17 [1.07–1.29] 0.0070 No. of chronic conditions** 0–1 43,130,164 14.3 [14.1–14.6] 1208 13.3 [11.7–14.9] 1.00 [REF] – 1.00 [REF] – 2–5 149,985,288 49.8 [49.5–50.1] 5366 59.1 [56.7–61.6] 1.28 [1.11–1.47] 0.0013 1.48 [1.36–1.61] 0.0002 6+ 108,103,076 35.9 [35.4–36.4] 2501 27.6 [25.1–30.0] 0.83 [0.70–0.98] 0.0465 1.19 [1.08–1.30] 0.0061 Season Winter 70,515,502 25.5 [25.5–25.6] 2014 24.4 [22.3–26.6] 0.95 [0.83–1.09] 0.5221 Spring 69,068,517 25.0 [25.0–25.0] 2081 25.3 [23.2–27.3] 1.00 [REF] – Summer 68,500,820 24.8 [24.8–24.8] 2098 25.5 [23.4–27.5] 1.02 [0.89–1.16] 0.8707 Fall 68,079,188 24.7 [24.6–24.7] 2045 24.8 [22.7–27.0] 1.00 [0.87–1.15] 0.9921 Hospital location* Metro > 1 million 81,073,540 31.6 [29.5–33.7] 2496 33.6 [29.5–37.6] 1.00 [REF] – 1.00 [REF] – Fringe/ 132,001,348 51.5 [49.5–53.5] 3977 53.5 [49.4–57.6] 0.98 [0.84–1.14] 0.8488 1.05 [0.99–1.12] 0.2563 metro < 1 million Micropolitan 26,864,671 10.5 [9.7–11.3] 638 8.6 [6.7–10.4] 0.77 [0.60–0.99] 0.0585 0.77 [0.69–0.87] 0.0005 Not metro or mic- 16,302,225 6.4 [6.0–6.7] 326 4.4 [3.2–5.6] 0.65 [0.49–0.87] 0.0071 0.71 [0.61–0.83] 0.0005 ropolitan Hospital region Northeast 61,250,129 20.3 [19.1–21.6] 1775 19.6 [16.6–22.5] 1.17 [0.95–1.43] 0.1887 0.99 [0.92–1.06] 0.8358 Midwest 70,747,314 23.5 [22.3–24.7] 1993 22.0 [18.8–25.1] 1.13 [0.92–1.39] 0.2949 0.90 [0.82–0.98] 0.0818 South 115,898,343 38.5 [36.8–40.1] 3980 43.9 [39.8–47.9] 1.38 [1.14–1.67] 0.0017 1.05 [0.97–1.13] 0.4310 West 53,322,742 17.7 [16.6–18.8] 1327 14.6 [12.3–16.9] 1.00 [REF] – 1.00 [REF] – Hospital teaching status Non-teaching 151,140,068 55.4 [53.6–57.1] 3490 43.8 [39.6–48.1] 1.00 [REF] – 1.00 [REF] –

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Table 1 (continued) Variable Primary inpatient diagnosis of PG No Yes Wtd freq % Prev [95% CI] Wtd freq % Prev [95% CI] Crude OR [95% CI] P Adj OR [95% CI] P

Teaching 121,781,970 44.6 [42.9–46.4] 4471 56.2 [51.9–60.4] 1.59 [1.36–1.86] 0.0002 1.59 [1.50–1.68] 0.0002 Hospital bed size Small 36,976,262 12.3 [11.7–13.0] 833 9.2 [7.4–11.1] 1.00 [REF] – 1.00 [REF] – Medium 74,211,375 24.7 [23.6–25.9] 1953 21.7 [18.9–24.4] 1.17 [0.93–1.47] 0.2398 1.22 [1.10–1.35] 0.0023 Large 188,753,209 62.9 [61.6–64.3] 6221 69.1 [65.9–72.3] 1.46 [1.18–1.81] 0.0011 1.47 [1.34–1.61] 0.0002

Wtd fred weighted frequency, yr years, REF reference, Prev prevalence, CI confdence interval, OR odds ratio, adj adjusted, PG pyoderma gangrenosum *Metropolitan: ≥ 1 urban cluster of population ≥ 1 million, fringe/metro: ≥ 1 urban cluster of population ≥ 50,000, but < 1 million; micropolitan: ≥ 1 urban cluster of population 10,000–49,999; not metropolitan or micropolitan: none of these **Chronic conditions were defned by HCUP as lasting 12 months or longer and meeting one or both of the following: places limitations on self- care, independent living, and social interactions and/or results in the need for ongoing intervention with medical products, services, and special equipment. Chronic condition count was calculated and provided by HCUP

Associated comorbidities was discharged routinely, though a subset (25.6%) was also discharged to home health care (Table 2). Among adults, PG was associated with markedly higher odds of having Takayasu’s arteritis (multivariable logistic regression; adjusted OR [95% CI] 26.30 [9.53–72.57]), Discussion Crohn’s disease (32.45 [29.19–36.06]), ulcerative coli- tis (32.06 [28.65–35.88]), subcorneal pustular dermatosis The present study demonstrated a substantial inpatient bur- (35.13 [4.89–252.60]), hidradenitis suppurativa (42.08 den of PG in the US, with increasing prevalence of hospi- [32.91–53.81]), and Behcet’s disease (47.69 [22.27–86.59]) talization for PG in adults over time, considerable disabil- in multivariable models. Other comorbidities with signif- ity and mortality risk, multiple comorbid health disorders, cantly higher odds included: granulomatosis with polyangii- and > $9 million annual cost of inpatient care. There were tis, autoimmune hepatitis, ankylosing spondylitis, rheuma- signifcant racial/ethnic and socioeconomic disparities in toid arthritis, systemic lupus erythematosus, scleroderma, hospitalization for PG. In particular, higher rates of hos- autoimmune hemolytic anemia, psoriasis, acne, peptic ulcer pitalization were found in PG patients who had black race/ disease, hematologic malignancy (including lymphoma and ethnicity, lower income, and publicly insured and uninsured. leukemia), monoclonal gammopathy of unknown signif- All of these associations remained signifcant in multivariate cance, myelodysplastic syndrome, polycythemia vera, and models. Hospitalization for PG likely occurs for several rea- osteomyelitis. In contrast, PG was associated with signif- sons. Patients with or without an established diagnosis of PG cantly lower odds of having solid malignancy, or HIV infec- may present to hospital emergency departments for evalu- tion (Fig. 2). ation and management of ulcerative lesions, pain control, improved wound care, and concern for infection. Most of Hospital course these issues could potentially be managed in the outpatient setting. However, PG patients may face barriers to outpa- The majority of adults with PG were classifed as having tient care, including high out-of-pocket costs, inadequate minor (64.4%) or moderate (25.7%) likelihood of dying transportation, and severe disability from their disease [9]. based on All Patient Refned Diagnosis-Related Group, The world-wide incidence has been estimated to be and moderate (52.5%) and major (28.7%) loss of function. around 3–10 cases per million per year, with a median age Among adults hospitalized for PG, 16.5% underwent skin of presentation at 59 years [1, 10]. In contrast, a recent study debridement, 21.8% had a skin biopsy performed, and 5.1% performed by Xu et al. measured age- and sex-standardized had a skin graft placed (Table 2). prevalence of PG among a 58 million US population-based Hospitalization with vs. without a primary diagnosis cohort to be 58 PG cases per 1,000,000 adults [11]. In our of PG was associated with signifcantly prolonged LOS study, the prevalence of hospitalization for PG in adults in adults (geometric mean [95% CI] 5.7 [5.4–5.9] vs. 3.5 ranged from 31 to 39 per million hospitalized adults, and [3.5–3.5] days, P = 0.0002). The majority of adults (58.4%) the mean age of people hospitalized with PG was 53 years.

1 3 Archives of Dermatological Research Association between pyoderma gangrenosum and health comorbidities. Survey logistic regression models were constructed regression withas the gangrenosum models were logistic and pyoderma independent variable and health gangrenosum comorbidities. Survey pyoderma Association between 2 Fig. (white, race (male, female), (continuous), sex models included age Multivariate estimated. comorbidity as the and 95% confdence intervals were Odds ratios dependent variable. the respective and 95% confdence intervals of theodds ratios adjusted Forest-plots estimated. and 95% confdence intervals were odds ratios Adjusted no) as covariables. status and insurance (yes, nonwhite), presented are

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Table 2 Hospital course for adults hospitalized with a primary diag- In addition, a previous study found that most of the PG nosis of pyoderma gangrenosum cases occurred in females (~ 76% of cases) [12]. Similarly, Variable Adults we found that female gender was associated with increased odds of hospitalization for PG. Wtd freq % Prev [95% CI] Previous case series demonstrated multiple comorbidities Diagnostic procedures on skin and subcutaneous tissue (skin biopsy associated with PG including infammatory bowel disease, included) hematological disorders, psoriasis, hepatitis, and solid organ Yes 1983 21.9 [19.8–24.0] malignancies [12–15]. In a study of 121 patients at three No 7092 78.1 [76.0–80.2] wound care centers in Germany, 14.1% had rheumatologic Skin biopsy comorbidities and 20.6% of patients had neoplasms of which Yes 1978 21.8 [19.7–23.9] 6.6% were classifed as hematological and 14.0% as solid No 7097 78.2 [76.1–80.3] neoplasms [16]. A retrospective multicentric analysis of 259 Skin debridement PG patients in Germany found that 25.5% of the patients had Yes 1495 16.5 [14.6–18.4] diabetes mellitus with some aspects of metabolic syndrome No 7579 83.5 [81.6–85.4] [7]. Our results also confrm the previous studies that found Skin graft associations of PG with infammatory arthritis, monoclonal Yes 465 5.1 [4.0–6.3] gammopathy of undetermined signifcance, myelodysplastic No 8610 94.9 [93.7–96.0] syndrome, polycythemia vera, hidradenitis suppurativa, pso- Ventilation riasis, thyroid disease, diverticulosis, peptic ulcer disease, Yes 53 0.6 [0.2–0.9] and Takayasu’s arteritis [12, 15, 17–19]. However, we did No 9022 99.4 [99.1–99.8] not fnd signifcant associations in hospitalized patients with Ventilation < 96 h PG with thyroid disease, polycystic ovarian syndrome, type Yes 39 0.4 [0.1–0.7] 1 diabetes mellitus, type II diabetes mellitus, or solid organ No 9036 99.6 [99.3–99.9] malignancies. Despite the lack of overall association with Ventilation > 96 h solid organ malignancies, PG may still be associated with Yes 14 0.2 [0.0–0.3] specifc types of solid malignancies and further studies are No 9061 99.8 [99.7–100.0] needed. Physical therapy PG is considered a neutrophilic dermatosis with an abun- Yes 174 1.9 [1.2–2.7] dance of neutrophils in the dermis [20], aberrant neutrophil No 8901 98.1 [97.3–98.8] chemotaxis, and neutrophilic dysfunction [21]. These mech- Mortality risk anisms may explain PG’s association with other disorders Minor 5801 64.4 [61.8–66.9] with neutrophilic dysfunction, such as HS [22]. Moreover, Moderate 2317 25.7 [23.4–28.0] neutrophilic dysregulation has been implicated in infam- Major 744 8.3 [6.9–9.6] matory bowel disease [23] and rheumatoid arthritis [24]. Extreme 152 1.7 [1.1–2.3] However, immune dysregulation in PG and its comorbidities Loss of function severity may derive from underlying autoinfammation [21]. Minor 1345 14.9 [13.3–16.5] The skin lesions of PG can occur before, simultaneously, Moderate 4730 52.5 [50.0–54.9] or after the presentation of the other systemic illnesses men- Major 2586 28.7 [26.4–31.0] tioned above. Therefore, it is important that clinicians con- Extreme 353 3.9 [3.0–4.9] sider evaluating PG patients for other systemic conditions. Patient disposition at discharge However, no formal guidelines exist for comorbidity screen- Routine 5293 58.4 [55.6–61.1] ing in PG. The previous suggestions included a complete Transfer, short-term hospital 172 1.9 [1.3–2.5] blood count, erythrocyte sediment rate, C-reactive protein, Transfer, SNF, ICF, or other facility 1093 12.1 [10.4–13.7] liver and renal function tests, protein electrophoresis, uri- Home health care 2321 25.6 [23.3–27.9] nary Bence Jones protein, a full hepatitis screen, a vasculi- Left against medical advice 110 1.2 [0.7–1.7] tis screen, cryoglobulins if the history is suggestive, and a Died 75 0.8 [0.4–1.2] coagulation screen to investigate for thrombotic causes of CI confdence interval, ICF intermediate care facility, SNF skilled ulceration. A chest X-ray was also suggested as a baseline nursing facility screen prior to systemic therapy and computed tomography if there was a suspicion for underlying malignancy [10]. Other recommendations included an antinuclear antibody titer to evaluate for the presence of systemic lupus erythematosus or collagen vascular disorders, antineutrophilic

1 3 Archives of Dermatological Research cytoplasmic antibodies to evaluate for granulomatous vascu- Funding This publication was made possible with support from the litis as a cause of ulceration, rheumatoid factor, and colonos- Agency for Healthcare Research and Quality, grant number K12 HS023011, the Dermatology Foundation. copy to evaluate for underlying infammatory bowel disease [25]. Formal guidelines for the screening and management Compliance with ethical standards of the comorbidities of PG are needed. The prevalence of hospitalization for PG may be an Conflict of interest None. underestimate due to diagnostic challenges. PG was previously considered to be a diagnosis of exclusion. However, international consensus criteria were recently developed that References require one major and four minor criterion to be met [26]. Further studies are needed to determine the validity and reli- 1. Monari P, Moro R, Motolese A et al (2018) Epidemiology of ability of these guidelines in clinical practice. PG was asso- pyoderma gangrenosum: results from an Italian prospective mul- ciated with prolonged hospitalization, which may be due to ticentre study. Int Wound J 15(6):875–879 a combination of both diagnostic and therapeutic difculties. 2. Vidal D, Puig L, Gilaberte M, Alomar A (2004) Review of 26 Some PG patients may be misdiagnosed as having diferent cases of classical pyoderma gangrenosum: clinical and therapeutic features. J Dermatol Treat 15(3):146–152 etiologies of ulcers and/or infections. Delayed consultation 3. Saracino A, Kelly R, Liew D, Chong A (2011) Pyoderma gan- by a dermatologist may result in unnecessarily prolonged grenosum requiring inpatient management: a report of 26 cases hospitalizations. Similarly, a previous study found that early with follow up. Australas J Dermatol 52(3):218–221 consultation by a dermatologist for patients with cellulitis 4. Brodell DW, Elfar JC, Mercurio MG (2015) Pyoderma gangrenosum and infammatory bowel disease: a cross-sectional inpatient led to more efcient diagnosis, decreased use of inappropri- socioeconomic study. J Am Acad Dermatol 73(5):877–880 ate antibiotics and reduced hospitalization [27]. Consulting 5. Kafenberger BH, Hinton A, Krishna SG (2018) The impact of dermatologists early in a patient’s hospitalization for cutane- underlying disease state on outcomes in patients with pyoderma ous ulcers may reduce the duration of hospitalization. gangrenosum: a national survey. J Am Acad Dermatol 79(4):659– 663.e652 Strengths of this study include a nationally representative 6. Kafenberger BH, Hinton A, Krishna S (2018) The validity of sample of > 63 million hospitalizations spanning 11 years. pyoderma gangrenosum ICD9-CM coding in hospital adminis- Potential weaknesses include lack of information about trative datasets. J Am Acad Dermatol. https://doi.org/10.1016/j. outpatient treatments and workup and how these impacted jaad.2018.05.007 7. Al Ghazal P, Herberger K, Schaller J et al (2013) Associated fac- hospitalization rates and course. PG was identifed using an tors and comorbidities in patients with pyoderma gangrenosum ICD-9-CM code, which may be subject to misclassifcation in Germany: a retrospective multicentric analysis in 259 patients. depending on the diagnosis confrmation methods used [6, Orphanet J Rare Dis 8:136–136 28]. We could not determine if the primary diagnosis of PG 8. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy was given by a dermatologist versus other physician, or what Stat Soc B (Methodological) 57(1):289–300 diagnostic criteria were used. Finally, we were also unable 9. Fife CE, Carter MJ (2012) Wound Care outcomes and associated to determine how many of the hospitalizations were due to cost among patients treated in us outpatient wound centers: data readmissions. However, the NIS is a large dataset with ran- from the US wound registry. Wounds 24(1):10–17 10. George C, Deroide F, Rustin M (2019) Pyoderma gangrenosum— dom sampling procedures from over 1000 hospitals in the a guide to diagnosis and management. Clin Med 19(3):224–228 United States. Therefore, the chance of capturing readmis- 11. Xu A, Balgobind A, Strunk A, Garg A, Alloo A (2019) Prevalence sions is very small, and thus, our data most likely represent estimates for pyoderma gangrenosum in the United States: an age- unique individual primary admissions for PG. and sex-adjusted population analysis. J Am Acad Dermatol 12. Binus AM, Qureshi AA, Li VW, Winterfeld LS (2011) Pyo- In conclusion, this study demonstrates a consider- derma gangrenosum: a retrospective review of patient character- able inpatient burden of PG in adults in the United States. istics, comorbidities and therapy in 103 patients. Br J Dermatol Improving diagnostic accuracy, outpatient access, treatment, 165(6):1244–1250 and wound care may potentially reduce healthcare costs for 13. Shahi V, Wetter DA (2015) Pyoderma gangrenosum associated with solid organ malignancies. Int J Dermatol 54(9):e351–e357 PG. Interdisciplinary collaboration and workup is warranted 14. Rodríguez-Zúñiga MJM, Heath MS, Gontijo JRV, Ortega-Loayza to reduce hospitalization and optimize care for PG patients. AG (2019) Pyoderma gangrenosum: a review with special empha- sis on Latin America literature. An Bras Dermatol 94(6):729–743 15. Ashchyan HJ, Butler DC, Nelson CA et al (2018) The association of age with clinical presentation and comorbidities of pyoderma Author contributions JIS had full access to all the data in the study gangrenosum. JAMA Dermatol 154(4):409–413 and takes responsibility for the integrity of the data and accuracy of 16. Jockenhöfer F, Herberger K, Schaller J et al (2016) Tricenter the data analysis. Study concept and design: JIS. Acquisition of Data: analysis of cofactors and comorbidity in patients with pyoderma JIS and SN. Analysis and interpretation of data: SN and JIS. Drafting gangrenosum. JDDG J Dtsch Dermatol Ges 14(10):1023–1030 of the manuscript: SN and JIS. Critical revision of the manuscript for 17. Niv D, Ramirez JA, Fivenson DP (2017) Pyoderma gangrenosum, important intellectual content: SN and JIS. Statistical analysis: JIS and acne, and hidradenitis suppurativa (PASH) syndrome with recur- SN. Obtained funding: JIS. rent vasculitis. JAAD Case Rep 3(1):70–73

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18. Zhang X, Jiao Y (2019) Takayasu arteritis with pyoderma gan- hfhs.org/contents/pyode rma-gangr enosu m-patho genes is-clini cal- grenosum: case reports and literature review. BMC Rheumatol features-and-diagnosis?search=pyoderma%2520gangrenosum 3(1):45 &source=searc h_resul t&selec tedTi tle=1~93&usage _type=defau 19. Phan JC, Hargadon AP, Salpeter SR (1996) Association between lt&display_rank=1#H4373 845 . Accessed 18 Mar 2020 (Updated pyoderma gangrenosum and psoriasis. Lancet 348(9026):547 January 15, 2019) 20. Ahronowitz I, Harp J, Shinkai K (2012) Etiology and management 26. Maverakis E, Ma C, Shinkai K et al (2018) Diagnostic criteria of of pyoderma gangrenosum. Am J Clin Dermatol 13(3):191–211 ulcerative pyoderma gangrenosum: a delphi consensus of inter- 21. Braswell SF, Kostopoulos TC, Ortega-Loayza AG (2015) Patho- national experts. JAMA Dermatol 154(4):461–466 physiology of pyoderma gangrenosum (PG): an updated review. 27. Li DG, Xia FD, Khosravi H et al (2018) Outcomes of early derma- J Am Acad Dermatol 73(4):691–698 tology consultation for inpatients diagnosed with cellulitis. JAMA 22. Byrd AS, Carmona-Rivera C, O’Neil LJ, et al (2019) Neutrophil Dermatol 154(5):537–543 extracellular traps, B cells, and type I interferons contribute to 28. Lockwood SJ, Li DG, Butler D, Tsiaras W, Joyce C, Mostaghimi A immune dysregulation in hidradenitis suppurativa. Sci Transl Med (2018) The validity of the diagnostic code for pyoderma gangreno- 11(508) sum in an electronic database. Br J Dermatol 179(1):216–217 23. Williams IR, Parkos CA (2007) Colonic neutrophils in infammatory bowel disease: double-edged swords of the innate immune Publisher’s Note Springer Nature remains neutral with regard to system with protective and destructive capacity. Gastroenterology jurisdictional claims in published maps and institutional afliations. 133(6):2049–2052 24. Mowat AG, Baum J (1971) Chemotaxis of polymorphonuclear leukocytes from patients with rheumatoid arthritis. J Clin Investig 50(12):2541–2549 25. Schadt C (2019) Pyoderma gangrenosum: pathogenesis, clinical features, and diagnosis. https://www-uptod ate-com.slade nlibr ary.

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