The impact of underlying disease state on outcomes in patients with pyoderma gangrenosum: A national survey

Accepted Manuscript The impact of underlying disease state on outcomes in patients with pyoderma gangrenosum: A national survey Benjamin H. Kaffenberger, MD, Alice Hinton, PhD, Somashekar Krishna, MD, MPH PII:

S0190-9622(18)30184-1

DOI:

10.1016/j.jaad.2018.02.007

Reference:

YMJD 12313

To appear in:

Journal of the American Academy of Dermatology

Received Date: 16 August 2017 Revised Date:

21 December 2017

Accepted Date: 6 February 2018

Please cite this article as: Kaffenberger BH, Hinton A, Krishna S, The impact of underlying disease state on outcomes in patients with pyoderma gangrenosum: A national survey, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.02.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The impact of underlying disease state on outcomes in patients with pyoderma gangrenosum: A national survey Benjamin H. Kaffenberger MD,1 Alice Hinton PhD,2 Somashekar Krishna MD, MPH 3 1

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Correspondence to: Benjamin H. Kaffenberger M.D. OSU Dermatology 1800 Zollinger Road, 3rd Fl. Columbus, OH, 43212 Phone: 614-293-1707

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Department of Internal Medicine, Division of Dermatology, The Ohio State University Wexner Medical Center 2 Division of Biostatistics, College of Public Health, The Ohio State University 3 Department of Internal Medicine, Division of Gastroenterology The Ohio State University Wexner Medical Center

Previous publication: None

Funding Sources: The study was supported in part, by Grant Number UL1TR001070 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award

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Conflict of Interest: BHK is an investigator for Biogen, Celgene, Eli Lilly Co, and XBiotech. The other investigators do not have conflicts of interest to disclose. Main Text Word Count: 1729 Number of Figures: 0

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Number of Tables: 4

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ABSTRACT

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Background: It is unclear if the underlying disease affects the outcomes in pyoderma

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gangrenosum.

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Objectives: To determine the impact of comorbid disease associations and concomitant

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procedural treatments on patient outcomes in PG patient-hospitalizations.

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Methods: A cross-sectional analysis of the Nationwide Inpatient Sample (NIS) for PG patient-

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hospitalizations from years 2002-2011, analyzing in-hospital mortality rate and health care

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resource utilization.

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Results: Inflammatory bowel disease was the most frequent comorbid association, followed by

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inflammatory arthritis, hematologic malignancies/dyscrasias, and vasculitis. Multivariable

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modeling showed that vasculitis and hematologic malignancy/dyscrasia, when compared to

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subjects with IBD, were associated with a 4-6 fold increased risk of in-hospital mortality while

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increasing healthcare resource utilization. Inpatient procedural interventions including skin

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grafts, biopsies, and debridement did not impact mortality and were associated with an increased

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length of stay.

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Limitations: The database does not account for outpatient follow-up, additionally there was a

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low rate of coded comorbid conditions.

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Conclusions: Comprehensive evaluation to determine the underlying comorbidity for patients

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with PG is important for patient risk stratification.

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Introduction

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Pyoderma gangrenosum (PG) has multiple underlying disease associations including

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inflammatory bowel disease, rheumatoid arthritis, monoclonal gammopathy, vasculitis,

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streptococcal infections, multiple myeloma, and acute myelogenous leukemia.1–8 It is unclear if

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the underlying comorbidities impact the prognosis or treatment course. Therefore, the primary

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objective is to evaluate if survival in PG is influenced by comorbidity.

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While long thought that debridement and grafting are strictly contraindicated,3,9 there is some

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evidence to support skin grafting and gentle debridement once the inflammation is quiescent.1,10

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Secondary objectives include the determination of whether skin biopsies and procedural

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techniques such as debridement or grafting, are associated with improvements in mortality,

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hospital length of stay, and hospital costs.

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Methods

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Patient Database

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The study utilized de-identified data and was exempt from the Institutional Review Board of The

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Ohio State University Wexner Medical Center. Variables of interest were queried from the

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Nationwide Inpatient Sample (NIS) from 2002-2011. The NIS is maintained as part of the

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Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and

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Quality.11 This is the largest all-payer inpatient care database in the United States and

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approximates a 20% stratified sample of nonfederal, acute-care hospitals encompassing over 8

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million discharges per year. Each discharge entry includes demographic features on the patient,

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hospital characteristics, primary and secondary diagnoses, in-hospital mortality, hospital cost,

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and length of stay.

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Study Population

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The study population consisted of all adult discharges, >17 years of age, hospitalized with

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pyoderma gangrenosum. This diagnosis was selected using the International Classification of

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Diseases, Ninth revision, Clinical Modifications codes (ICD-9CM) of 686.01 as a primary or

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secondary diagnosis during the hospitalization. Comorbidities of interest were defined as

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inflammatory bowel disease (IBD), inflammatory arthritis (IA), small vessel vasculitis, and

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leukemia and gammopathies (classified as hematologic dyscrasia). We chose to include small

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vessel vasculitis as an associated condition for pyoderma gangrenosum based on case reports and

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experience, particularly given that IgA paraproteinemias may link both morphologies and that

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lymphocytic vasculitis can be a diagnostic criterion. They underwent an algorithm in that order

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for attribution to PG (Supplemental Table 1). Patients with pregnancy related codes, and

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concomitant codes related to a potential misdiagnosis including, medium vessel vasculitis, deep

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fungal infections, cutaneous T and peripheral T-cell lymphomas, leukemia cutis, Langerhans cell

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histiocytosis, anti-phospholipid antibody syndrome, and livedoid vasculopathy and related codes

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were excluded. Procedures were included in this analysis if they were listed on the patient

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discharge and were based on appropriate ICD-9-CM codes including skin biopsy, debridement,

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skin graft, and ostomy management (Supplemental Table 1). Typical demographic patient

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variables were included and comorbidity was assessed using the Elixhauser score, a validated

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instrument for assessing inpatient data for patient outcomes from a set of 30 comorbid

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conditions.12 The comorbidity score was dichotomized as <3 vs ≥3 comorbidities. Hospital

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procedure volume was categorized as high for those at or above the 75th percentile for skin

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biopsies, low for those between 1-74%, and none for those that billed for 0 skin biopsies during

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the years analyzed.

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Statistical Analysis

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SAS 9.4 (SAS Institute, Cary, NC) was used to perform all analyses, employing appropriate

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survey estimation commands and strata weights. Sample data for continuous variables were

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stated as means with standard deviations (SDs). Categorical variables were tested for statistical

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significance with χ2 tests, whereas differences in continuous variables were analyzed with t-tests.

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Statistical significance was defined by P<0.05. Linear regression was used to evaluate the effect

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of underlying comorbidities and procedures on LOS and hospital cost and logistic regression was

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used to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for in-

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hospital mortality. Multivariable regression models were developed using stepwise methodology

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where all variables in supplemental table 2 with the exception of the individual Elixhauser

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comorbidities were eligible for inclusion and adjusted for variables significantly associated with

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mortality, length of stay, and cost in the models.

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Results

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Demographics:

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After excluding similar ulcerative conditions, 31 885 hospitalizations for patients with a

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diagnosis of pyoderma gangrenosum were identified during years 2002-2011. The patients were

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predominately female, with a mean age of 55 ± 0.31 years. The groups spanned the spectrum of

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race, insurance type, and hospital region (Supplemental Table 2). Most patients had 2 or fewer

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Elixhauser comorbidities. The most common underlying disease was IBD with over 26% of

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patient hospitalizations followed by patients with inflammatory arthritis, hematologic

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malignancy and dyscrasias, and small vessel vasculitis, while 61% of patient-hospitalizations did

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not have a coded well-described comorbidity. The incidence of streptococcal infections and

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intestinal blind loop syndromes were < 1%. Multiple complications were associated with

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hospitalizations for PG: a chronic wound in 28%, cellulitis in 27%, sepsis and systemic

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inflammatory response syndrome (SIRS) in 7% and 5% respectively. Stoma complications were

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noted in 6%. The vast majority of hospitalizations did not have cutaneous procedures

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documented, however, 12% underwent a skin biopsy, 11% had debridement, and 3% had a skin

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graft. There was a disproportionate amount of PG diagnosed in the top quartile of hospitals for

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skin biopsies with nearly 60% of the diagnoses. Lastly, 731 patients expired in this cohort

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comprising 2% of the population. The hospitalization outcomes for the entire cohort include a

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mean hospitalization of 8.15 ± 0.14 days and mean cost of $13 159 ± 300.

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Multivariable Logistic Regression Modeling for Mortality

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The diagnosis of small vessel vasculitis, OR 6.0, 95% CI [2.63-13.69] and hematologic

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dyscrasias, OR 4.31, 95% CI [1.78-10.43] and all others, OR 2.23, 95% CI [1.21-4.11] in

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comparison to IBD were associated with increased risk of hospitalized patient mortality, while

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inflammatory arthritis was not. In addition, sepsis OR 12.43, 95% CI [8.65-17.86] and increasing

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age OR 1.04, 95% CI [1.03-1.05] were associated with patient mortality. In comparison, cellulitis

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was inversely associated with mortality risk OR 0.58, 95% CI [0.39-0.86] (Table 1).

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Multivariable Linear Regression Modeling for Length of Stay

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Patients with high Elixhauser comorbidity scores were associated with longer hospitalizations by

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2.14 days, 95% CI [1.51-2.78], as were sepsis by 8.89 days, 95% CI [6.88-10.91], stoma

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complications by 2.67 days, 95% CI [0.74-4.61], chronic wound codes by 1.76 days, (1.11-2.40),

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and the diagnosis of an underlying small vessel vasculitis by 2.17 days [0.12-4.23] or

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hematologic dyscrasia by 2.22 days [0.14-4.29] as compared to IBD. When looking at

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procedures, all were associated increased length of hospitalization, patients that received skin

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biopsies by 2.87 days [1.82-3.91], debridement by 5.32 days [3.96-6.68], or skin grafts by 7.93

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days [4.14-11.72] (Table 2).

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Multivariable Linear Regression Modeling for Hospital Cost

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Hospitalizations with higher Elixhauser comorbidity scores were associated with increased

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hospitalization costs of $4 321 [2 948- 5 694], while the comorbidities vasculitis $5 981 [67 -

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11896], hematologic dyscrasia $7 715 [1 775 – 13 655] also increased the costs respectively

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compared to the IBD reference patients. Hospitalizations involving debridement, skin biopsy,

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and skin grafting were consistently more expensive. In addition, hospitalization costs were

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increased with sepsis $22 448 [17 659 - 27 237], post-surgical complications $11 463 [2 319 – 20

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608] and patients at centers that were categorized as high skin biopsy volume $1 874 [293 – 3

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Discussion

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Previous studies have demonstrated the high mortality rate in patients with PG, over 15% in an 8

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year longitudinal study.1 The present study demonstrates an in-hospital mortality risk of around

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2% with significant variation based on comorbidities. It confirms that there is important

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prognostic value that is lost in the event that a patient is not thoroughly evaluated for a

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monoclonal gammopathy, myeloma, or leukemia. Interestingly, cellulitis was associated with a

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decreased mortality risk, but similar associations are reported in psoriasis hospitalizations.14 This

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may indicate that there is a high rate of misdiagnosis or an overstated systemic risk from the

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coded diagnosis of cellulitis.

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From the procedure analyses, skin biopsies were performed in a minority of patient-

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hospitalizations, however, many patients may have already carried the diagnosis of PG. In the

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hospital setting, the skin biopsy was associated with longer hospitalization and higher costs. This

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may be a surrogate for an initial or more thorough evaluation. Previous studies have also

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demonstrated the association of skin biopsies with longer hospitalizations.15 Similar to skin

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biopsies, skin grafts and debridement were actually associated with increased lengths of stay and

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costs without benefits in mortality.

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Multiple limitations exist in this current study, 60% of patients did not have a classically

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associated diagnosis by coding. This could represent coding error, unevaluated comorbidities, or

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even misdiagnosis. The validation of this disease using cross-sectional data is challenging, but

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coding data by general physicians in England has demonstrated a 50-75% positive predictive

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value in the coded diagnosis of PG, and we suspect our outcomes may be higher with the benefit

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of more specialists.7 Further, 68% of patient hospitalizations for PG were within hospitals that

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were in the top quartile for skin biopsies volume, indicating that most probably had access to

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dermatologists to make this specialized diagnosis. From the procedural aspect, its value may be

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understated without being able to follow patients longitudinally. Lastly, we hoped to study rare

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associations such as pneumonitis and PG, but such complications were so rarely coded, that we

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could not reliably quantify outcomes in this setting.

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In conclusion, mortality risk varied substantially among patients with small vessel vasculitis and

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hematologic malignancy/dyscrasia in comparison with patients with IBD and inflammatory

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arthritis. This emphasizes the need for comprehensive diagnostic evaluation. Procedural

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treatments did not show a benefit in this setting but ought to be studied further using longitudinal

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databases.

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Acknowledgements

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The content is solely the responsibility of the authors and does not necessarily represent the official

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views of the National Institutes of Health.

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Funding/Support: The study was supported in part, by Grant Number UL1TR001070 from the

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National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and

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Translational Sciences Award .

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Financial Disclosure: Dr. Benjamin Kaffenberger serves as an investigator for Biogen, Celgene,

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Eli Lilly Co, and Xbiotech.

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References

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Table 1: Multivariable logistic regression model for in-hospital mortality in patient hospitalizations for PG. Abbreviations: IBD – Inflammatory Bowel Disease

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Table 2: Multivariable linear regression model for length of stay in patient hospitalizations for PG. Abbreviations: IBD – Inflammatory Bowel Disease Table 3: Multivariable linear regression model for cost in patient hospitalizations for PG

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Supplemental Table 1: ICD-9CM codes used in study methodology for diagnosis of PG, associated comorbidities, and exclusion of similar diagnoses, and procedure codes

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Supplemental Table 2: Demographics of 31 885 patient hospitalizations for pyoderma gangrenosum. AIDS – Aquired immunodeficiency syndrome, AHRQ – Agency for Healthcare Research and Quality, PG – pyoderma gangrenosum, IBD – Inflammatory Bowel Disease,

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AHRQ – Agency for Healthcare Research and Quality AIDS – Aquired immunodeficiency syndrome IA – Inflammatory Arthritis IBD – Inflammatory Bowel Disease NIS – Nationwide Inpatient Survey PG- pyoderma gangrenosum SIRS – Systemic Inflammatory Response Syndrome

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List of Abbreviations:

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Table 1: Multivariable logistic regression model for in-hospital mortality in patient hospitalizations for PG. OR 95% CI p-value Age 1.04 (1.03, 1.05) <0.001 Comorbidities <0.001 IBD Reference Inflammatory Arthritis 0.89 (0.31, 2.57) (2.63, Vasculitis and Henoch Schonlein Purpura 13.69) 6.00 (1.78, Hematologic malignancy and Dyscrasia 4.31 10.43) Others 2.23 (1.21, 4.11) (8.65, Sepsis 12.43 17.86) <0.001 Cellulitis 0.58 (0.39, 0.86) 0.007

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250 251 252 253 254 255 256

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Table 2: Multivariable linear regression model for length of stay in patient hospitalizations for PG. Days 95% CI p-value Elixhauser comorbidity score <0.001 <3 Reference ≥3 2.14 (1.51, 2.78) Comorbidities 0.014 IBD Reference Inflammatory Arthritis -0.52 (-1.42, 0.38) Vasculitis and Henoch Schonlein 2.17 (0.12, 4.23) Purpura Hematologic malignancy and 2.22 (0.14, 4.29) Dyscrasia Others -0.02 (-0.64, 0.60) Sepsis 8.89 (6.88, 10.91) <0.001 Stoma complications 2.67 (0.74, 4.61) 0.007 Chronic Wound 1.76 (1.11, 2.40) <0.001 Skin graft 7.93 (4.14, 11.72) <0.001 Skin biopsy 2.87 (1.82, 3.91) <0.001 Debridement 5.32 (3.96, 6.68) <0.001

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Table 3: Multivariable linear regression model for cost in patient hospitalizations for PG. $ 95% CI p-value Hospital region <0.001 Northeast Reference Midwest -3,373 (-5,281, -1,465) South -3,870 (-5,705, -2,035) West 1,482 (-1,151, 4,114) Elixhauser comorbidity score <0.001 <3 Reference ≥3 4,321 (2,948, 5,694) Comorbidities 0.037 IBD Reference Inflammatory Arthritis 365 (-1,633, 2,364) Vasculitis and Henoch Schonlein 5,981 (67, 11,896) Purpura Hematologic malignancy and 7,715 (1,775, 13,655) Dyscrasia Others 61 (-1,258, 1,381) Sepsis 22,448 (17,659, 27,237) <0.001 Stoma complications 6,717 (2,532, 10,903) 0.002 Post Surgical Complication 11,463 (2,319, 20,608) 0.014 Skin graft 7,836 (2,549, 13,124) 0.004 Skin biopsy 3,952 (2,062, 5,842) <0.001 Debridement 8,513 (6,174, 10,852) <0.001 Biopsy procedure volume 0.027 None Reference Low (1-10 per year) 704 (-941, 2,348) High (>10 per year) 1,874 (293, 3,454)

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Supplemental Table 1: ICD-9CM codes used in study methodology for diagnosis of PG, associated comorbidities, and exclusion of similar diagnoses, and procedure codes

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Hyperbaric oxygen Debridement Intra-lesional injection Granulomatosis with polyangiitis and related conditions / Polyarteritis nodosa and related conditions Sporotrichosis and deep cutaneous fungal infections Anaplastic large cell lymphoma, cutaneous tcell lymphoma, peripheral t-cell lymphomas Leukemia Curtis Langerhans cell histiocytosis Anti-phospholipid antibody syndrome / Livedoid vasculopathy Wound Infection

DX1-DX25

273.xx; 289.89 579.2 038.xx 995.91, 995.92 569.xx 495.9 516.8

DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25

379.xx 997.6x 996.52, 996.55 998.31 E878.2 86.6x 86.7x E878.5 86.11 E878.3 46.4x 93.95 86.22, 86.28 83.98 446.xx

DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 ECODE1-ECODE4 PR1-PR15 PR1-PR15 ECODE1-ECODE4 PR1-PR15 ECODE1-ECODE4 PR1-PR15 PR1-PR15 PR1-PR15 PR1-PR15 DX1-DX25

114.xx-117.xx

DX1-DX25

200.6, 202.xx

DX1-DX25

709.8 202.xx 289.81

DX1-DX25 DX1-DX25 DX1-DX25

686.xx

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Pedicle grafts/flap Amputation Skin biopsy Stoma relocation/revision

NIS Variables DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25 DX1-DX25

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034.0, 038.0, 463, 474.xx

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PG IBD Acute myeloid leukemia Multiple myeloma Vasculitis and Henoch Schonlein Purpura Inflammatory Arthritis Monoclonal gammopathy of unknown significance Strep carriage, chronic tonsillitis, and nonacute infections Hypergammaglobulinemia Intestinal blind loop syndrome Sepsis Systemic inflammatory response syndrome Stoma complications Unspecified interstitial pneumonitis Other specified alveolar and pareitoalveolar pneumonopathies cavitary pneumonia Ocular complications Amputation stump complication Skin graft complication Flap/surgical wound complication Skin graft

ICD-9 Codes 686.01 555.xx, 556.xx 205.xx, 206.xx, 208.xx 203.xx 287.xx 714.xx 273.1

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682.xx 707.xx

DX1-DX25 DX1-DX25

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Cellulitis Chronic Wound

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Supplemental Table 2: Demographics of 31 885 patient hospitalizations for pyoderma gangrenosum PG Patients N = 31,885 Age (mean, SE) 55.31 0.31 Gender Male 10,474 32.87% Female 21,386 67.13% Race White 18,139 56.89% Black 4,444 13.94% Hispanic 1,721 5.40% Other 7,580 23.77% Income quartile 1 7,824 25.03% 2 8,089 25.87% 3 7,791 24.92% 4 7,559 24.18% Type of insurance Medicare 14,568 45.81% Medicaid 4,005 12.59% Private 10,361 32.58% Other 9.02% 2,867 Hospital type Rural 3,058 9.65% Urban nonteaching 12,059 38.06% Urban teaching 16,566 52.29% Hospital size Small 3,302 10.42% Medium 6,761 21.34% Large 21,619 68.24% Hospital region Northeast 5,924 18.58% Midwest 7,860 24.65% South 12,563 39.40% West 5,537 17.37% Elixhauser comorbidity score <3 16,886 66.43% ≥3 8,534 33.57% COMORBIDITIES (hierarchy) IBD Inflammatory Arthritis Vasculitis and Henoch Schonlein

8,453 2,345 795

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Purpura Hematologic malignancy and Dyscrasia Others

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2.78%

19,405

60.86%

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PROCEDURES Skin graft Skin biopsy Debridement None of the above

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COMPLICATIONS / ASSOCIATED DIAGNOSES AND OUTCOMES Sepsis 2,136 6.70% Systemic inflammatory response 1,628 5.10% syndrome Stoma complications 1,754 5.50% Post Surgical Complication 267 0.84% 100.00 Wound Infection 31,885 % Cellulitis 8,598 26.96% Chronic Wound 8,872 27.82% Mortality 731 2.30% Length of Stay (mean, SE) 8.15 0.14 Cost (mean, SE) 13,159 300

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SKIN BIOPSY PROCEDURE VOLUME None Low (1-10 per year) High (>10 per year)

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AHRQ ELIXHAUSER COMORBIDITIES AIDS Alcohol abuse Anemia Rheumatoid arthritis / collagen vascular disease Chronic blood loss Congestive heart failure Chronic lung disease Coagulopathy Depression

898 3,834 3,518 24,913

2.82% 12.02% 11.03% 78.14%

1,509 11,783 18,593

4.73% 36.95% 58.31%

51 613 9,186

0.16% 1.94% 29.05%

3,640

11.51%

859 2,891 5,199 1,495 4,184

2.72% 9.14% 16.44% 4.73% 13.23%

ACCEPTED MANUSCRIPT

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18.36% 6.00% 4.23% 43.16% 10.34% 4.11% 0.66% 24.88% 0.94% 4.75% 1.45% 12.30% 7.43% 3.94% 1.53% 9.15% 1.35% 0.25% 4.08% 7.80%

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5,806 1,899 1,339 13,652 3,271 1,299 210 7,869 297 1,501 457 3,891 2,349 1,246 483 2,895 427 78 1,291 2,467

M AN U

Diabetes mellitus Diabetes with chronic complications Drug abuse Hypertension Hypothyroidism Liver disease Lymphoma Fluid and electrolyte disorders Metastatic cancer Neurological disease Paralysis Obesity Peripheral vascular disease Psychoses Pulmonary circulation disorders Renal failure Solid tumor without metastasis Peptic ulcer disease Valvular disease Weight loss

ACCEPTED MANUSCRIPT

What is known: Pyoderma gangrenosum has many underlying disease associations. What this adds: Pyoderma gangrenosum patients who have underlying hematologic cancers, dyscrasias,

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and vasculitis, have worse hospital outcomes compared to patients with inflammatory bowel disease or inflammatory arthritis.

Impact on care: There is a need for comprehensive evaluation for risk stratification in patients with

AC C

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pyoderma gangrenosum.