Author's Accepted Manuscript

Chronic Prostate Inflammation is Associated with Severity and Progression of

Benign Prostatic Hyperplasia, Lower Urinary Tract Symptoms and Risk of Acute
Urinary Retention

J. Curtis Nickel , Claus G. Roehrborn , Ramiro Castro-Santamaria , Stephen J.

Freedland , Daniel M. Moreira

PII: S0022-5347(16)30760-1
DOI: 10.1016/j.juro.2016.06.090
Reference: JURO 13842

To appear in: The Journal of Urology

Accepted Date: 27 June 2016

Please cite this article as: Nickel JC, Roehrborn CG, Castro-Santamaria R, Freedland SJ, Moreira
DM, Chronic Prostate Inflammation is Associated with Severity and Progression of Benign Prostatic
Hyperplasia, Lower Urinary Tract Symptoms and Risk of Acute Urinary Retention, The Journal of
Urology (2016), doi: 10.1016/j.juro.2016.06.090.

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 ACCEPTED MANUSCRIPT

Chronic Prostate Inflammation is Associated with Severity and Progression of Benign

Prostatic Hyperplasia, Lower Urinary Tract Symptoms and Risk of Acute Urinary Retention

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J. Curtis Nickel, Claus G. Roehrborn, Ramiro Castro-Santamaria, Stephen J. Freedland, Daniel M.
Moreira

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Affiliations:
Department of Urology, Queen's University, Kingston, ON, Canada

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Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA
GlaxoSmithKline Inc., Global R&D Unit, King of Prussia, PA, USA

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Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Department of Urology, Mayo Clinic, Rochester, MN, USA
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ClinicalTrials.gov Identifier: NCT00056407

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Abstract

INTRODUCTION AND OBJECTIVES: We evaluated associations between histological prostate

inflammation and development and progression of BPH/LUTS in men randomized to placebo in

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the REDUCE study over a 4-year period.

METHODS: The association of acute and chronic inflammation detected on baseline biopsies

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and BPH related parameters (IPSS, prostate volume) at multiple time points over 4 years in men

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randomized to placebo enrolled in the REDUCE prostate cancer prevention study was analyzed

with Students t test. The association of inflammation with newly developed BPH/LUTS and BPH

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progression in patients with existing BPH/LUTS was analyzed with uni- and multivariable Cox
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model.

RESULTS: Acute and chronic inflammation was seen in baseline negative biopsies of 641 (15.6%)
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and 3216 (78.3%) of 4109 men in study. Chronic but not acute inflammation was associated
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with slightly higher baseline IPSS (difference=0.6, p=0.001) and larger prostate volume
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(difference=3.2cc, p<0.001), a difference noted throughout the study interval. The presence of

acute and chronic inflammation was not associated with the incidence of BPH/LUTS in men
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without BPH/LUTS at baseline or the progression of symptomatic BPH in men who had

BPH/LUTS at baseline but an association was observed with more severe inflammation. Chronic
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inflammation at baseline was associated with increase risk of AUR (HR=1.6-1.8, p=0.001).
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CONCLUSIONS: Our longitudinal evaluation of REDUCE patients randomized to placebo for 4

years confirmed that chronic inflammation is associated with severity and progression of BPH

and BPH/LUTS outcomes.

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Introduction:

More than two decades ago, we suggested that histological inflammation of the

prostate gland might be implicated in the etiology and pathogenesis of benign prostatic

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hyperplasia (BPH), along with static (prostatic enlargement) and dynamic (smooth muscle

tension) factors known to cause benign prostatic enlargement (BPE) and associated lower

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urinary tract symptoms (LUTS) [1]. Our previous cross-sectional examination of baseline data

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from the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, a 4-year, phase 3,

placebo-controlled study to determine if daily dutasteride 0.5 mg reduces the risk of biopsy

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detectable prostate cancer [2], showed a relationship between the degree of chronic
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inflammation and BPH/LUTS [3]. These findings have since been corroborated. Robert et al [4]

demonstrated that IPSS and prostate volume were higher in men with high grade inflammation.
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It has also been suggested that histological prostate inflammation may be associated with
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progression of clinical BPH. In a subgroup of men in the Medical Therapies of Prostate

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Symptoms study (MTOPS) [5] with baseline biopsies, the presence of inflammation predicted

BPH progression events such as symptom worsening, BPH-related surgery in placebo-treated

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patients and particularly AUR [6]. Other studies have shown that prostate inflammation

detected in transurethral resection of prostate specimens is more prevalent in patients with

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urinary retention compared to those with only LUTS [7,8]. Men with higher grade inflammation
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may have a greater risk of medical treatment failure and risk of BPH related surgery. [9].

The entrance criteria for REDUCE [2] included the requirement of a prostate cancer

negative biopsy prior to enrolment. This report examines the 4-year longitudinal association

between LUTS, development of new BPH/LUTS, progression of existing BPH/LUTS, prostate

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volume, AUR and histological prostate inflammation in the men randomized to placebo in the

REDUCE population.

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Methods:

The design of REDUCE was published previously [2]. In brief, eligible men were aged 50-

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75 years, had serum prostate-specific antigen (PSA) 2.5 or 3.0ng/mL according to age (50-60

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and 60-75 years, respectively) but 10ng/mL, one single negative prostate biopsy (6 to 12

cores) within 6 months of enrollment. Men were excluded if they had history of prostate

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cancer, high-grade intraepithelial neoplasia, atypical small acinar proliferation, prostate volume
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(PV) > 80 mL, had undergone previous prostate surgery or had an International Prostate

Symptom Score 25 or 20 on alpha-blockers. At the screening and randomization visits, data

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on demographics, medical history (including self-reported history of BPH), physical exam, PV

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(measured by ultrasonography), PSA, international prostate symptom score (IPSS), quality of

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life, peak urinary flow, and post-void residual (PVR) were collected. Participants were

randomized in a double-blind fashion to receive orally either dutasteride 0.5mg or placebo daily
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and followed every 6 months for 4 years. Baseline biopsies had been performed before the

start of the study and were reread centrally (at Bostwick Laboratories). Acute and chronic
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prostate inflammations were coded as present or absent [3,10]. Chronic inflammation

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consisted mainly of lymphocytes and a variable number of plasma cells and macrophages.

Acute inflammation consisted of neutrophillic infiltrate. Patients were followed every 6 months

in clinical visits where peak urinary flow, post-void residual, IPSS, and quality of life were

obtained. Medical and surgical history was also updated. The protocol was approved by the
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institutional review board at each research site, and all participants provided written informed

consent. Of the 8231 men enrolled in the study, 4126 (50.1%) were randomized to receive

placebo and were included in the study. We excluded 17 (<1%) men due to missing data on

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baseline acute and/or chronic inflammation which resulted in a final study sample of 4109 men.

Among patients without baseline BPH/LUTS (based on no self-reported history of

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BPH/LUTS, medical treatment for BPH, or baseline IPSS 8), the development of BPH/LUTS was

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defined as an IPSS report > 14 points, any surgical procedure for BPH (transurethral

prostatectomy, open prostatectomy, urethral balloon dilation, and laser prostatectomy), or the

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start of a drug for BPH (any uroselective -blockers such as tamsulosin or alfuzosin, any 5-
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reductase inhibitor such as finasteride, or any non-uroselective -blockers in addition to one

IPSS report > 14 or two IPSS reports 12 points before the start of medication)[2]. A post hoc
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analysis included subjects with an IPSS report of > 8 points (included mild BPH/LUTS). Among
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patients who met the definition of BPH/LUTS at baseline, progression of BPH/LUTS was defined
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as an increase 4 points from baseline IPSS, any surgical procedure for BPH, or the start of a

new drug for BPH. AUR was determined by patient or investigator reports.
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Univariable comparisons of baseline characteristics between men with and without

baseline acute and chronic prostate inflammations were performed using chi-square test for
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categorical data and Students t test for continuous variables. The association of baseline acute
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and chronic baseline inflammation with IPSS and prostate volume at multiple time points were

plotted, and evaluated with Students t test at baseline, and the differences in changes from

baseline were evaluated with analysis of covariance. The association of acute and chronic

inflammation in baseline prostate biopsies with time to the development and progression of
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BPH/LUTS and development of AUR was estimated and plotted with the Kaplan-Meier method

and compared between groups with log-rank test in univariable analysis and with Cox

proportional hazards model in both uni- and multivariable analyses. Multivariable analysis were

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controlled for baseline age (continuous, in years), race (White or other), body-mass index (BMI,

continuous, in kg/m2), digital rectal exam (DRE, coded as normal or abnormal), Prostate volume

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(PV, continuous, in cm3), PSA (continuous, in ng/mL), IPSS (continuous), quality of life

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(continuous), peak urinary flow (continuous, in mL/s), and Post Void Residual (PVR, continuous,

in mL). All covariates were determined at baseline. All statistical analyses were performed using

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R 3.2.1 (R Foundation for Statistical Computing, Vienna, Austria). A P < 0.05 was considered to
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indicate statistical significance.
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Results:
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Of the 4109 men include in the study, 3733 (90.8%) were White. The mean (standard
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deviation [SD]) age and body-mass index were 62.7 years (6.1) and 27.4 Kg/m2 (4.2),

respectively. The mean (SD) PSA and PV were 5.9 ng/mL (2.0) and 45.8 cm3 (18.8),
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correspondingly. The mean (SD) peak flow and PVR were 14.7 mL/s (19.5) and 46 mL (48),

respectively.
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A total of 2613 (63.6%), 38 (0.9%), 603 (14.7%), and 855 (20.8%) men had only baseline
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chronic inflammation, only baseline acute inflammation, both and none, respectively. Acute

baseline inflammation (observed in 641; 15.6%) was associated with younger age, lower

baseline PSA levels, and slightly better baseline quality of life (all P < 0.05) (Table 1). Chronic

baseline inflammation (observed in 3216; 78.3%) was associated with older age, non-White
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race, lower baseline PSA levels, larger prostates, higher baseline IPSS, worse baseline quality of

life, and higher baseline PVR (all P < 0.05) (Table 2).

Figures 1A and 1B depict the association of IPSS at multiple time points with acute and

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chronic baseline inflammation, respectively. Acute baseline inflammation was unrelated to IPSS

at any time. Chronic baseline inflammation was associated with higher IPSS at baseline, which

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remained relatively stable throughout the study interval. Figures 2A and 2B depict the

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association of prostate volume at multiple time points with baseline acute and chronic

inflammation, respectively. Acute baseline inflammation was associated with lower prostate

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volumes at baseline and this association remained relatively unchanged over time. Conversely,
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chronic baseline inflammation was associated with larger prostates at baseline as well as

increased prostate volume changes from baseline.

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A total 797 men did not fulfill the definition of baseline BPH/LUTS and were included in
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the analysis of the development of BPH/LUTS. After a median follow-up of 49.9 months, 93 men
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developed BPH/LUTS. Acute and chronic inflammations were not associated with the incidence

of BPH/LUTS in either uni- or multivariable analyses (Figure 3A and 3B, and Table 3). In a post-
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hoc analysis, this association of baseline prostate inflammation with development of BPH/LUTS

did not change when we revised the definition to include IPSS > 8 (supplemental Table 1). A
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total of 2659 men had fulfilled the definition of BPH/LUTS at baseline and were included in the
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analysis of BPH/LUTS progression. After a median follow-up of 41.4 months, 1264 men

developed progression of BPH/LUTS. The presence of acute and chronic inflammation was not

associated with the progression of BPH/LUTS in either uni- or multivariable analyses (Figure

4A.B, and Table 3). However, a post-hoc analysis evaluating the severity of baseline chronic
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inflammation showed a weak association between moderate/marked inflammation and

development and/or progression of BPH/LUTS in multivariable analyses (Supplemental table 2

and Supplemental Figure 1).

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Of the 4109 men included in the study, 262 developed AUR over a median follow-up of

48.4 months. Of the 2659 men with history of BPH/LUTS at baseline, 221 developed AUR over a

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median follow-up of 48.4 months. Chronic inflammation at baseline was associated with

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shorter time to risk of AUR (p=0.001) in the entire placebo group (Supplemental Figure 2A) and

in subjects with baseline clinical BPH/LUTS (Supplemental Figure 2B). The absolute difference

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between groups is small, however, the relative difference is clinically meaningful, as suggested
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by the HRs between 1.6 and 1.8 (Table 4). This difference is quite obvious in the Figures 5A and

5B showing the cumulative incidence and confidence intervals for AUR as a function of baseline
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chronic inflammation.
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Discussion:

Our longitudinal evaluation of REDUCE patients randomized to placebo for 4 years

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confirmed that chronic inflammation is associated with higher IPSS scores and larger prostate

volume. However, we were not able to show that baseline inflammation dichotomized to
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presence of absence of acute or chronic inflammation predicts development or progression of

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BPH/LUTS, although men with baseline chronic inflammation had an increased risk of larger

prostate size compared to baseline and of AUR over 4 years. Furthermore post-hoc analyses

examining the impact of inflammation severity showed a weak association between

moderate/severe prostate inflammation at baseline and BPH/LUTS progression over 4 years.

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While we still do not fully understand the pathogenesis of BPH, multiple partially

overlapping and complementary theories have been proposed. While the nervous, endocrine

and immune systems have all been implicated, only aging and androgens are accepted as

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established risk factors for the development of BPH and BPE, which can lead to LUTS in men as

they age. One of the most intriguing hypotheses is that inflammation is involved in the etiology

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of BPH and promotes BPH progression [11]. Inflammation can theoretically lead to the

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development and progression of BPH through a number of proposed mechanisms [12]. These

include immunologic [13], structural [14] or the observed link with the metabolic syndrome

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[15,16]. Our study did confirm this predicted association in that we showed men with evidence
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of chronic inflammation had higher mean IPSS scores and prostate volumes compared to men

without inflammation. While the just the presence of chronic inflammation did not predict a
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general increase in population mean IPSS scores over time, incidence or progression of
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BPH/LUTS, the severity of inflammation was associated with development of new BPH/LUTS in
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initially asymptomatic men, as well as clinical progression of BPH/LUTS. Chronic inflammation

appeared to be associated with an increase in prostate volume (from baseline) compared to

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men without inflammation over time and a real association with increased risk of AUR over 4

years.
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The major limitation of this study was that it was a cancer prevention study and our

analysis was a post hoc evaluation of BPH endpoints in the placebo group only. We have shown

that patients randomized to dutasteride in this longitudinal analysis would have had their BPH

endpoints reduced over time [17] and therefore complicated any evaluation of the effect of

baseline inflammation on BPH/LUTS progression if we had included the treatment arm. Men
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with severe BPH (PV > 80cm3 and/or baseline IPSS 25 or 20 on alpha-blockers) were not

included in REDUCE. We have not addressed the confounding associations between prostate

inflammation, BPE, BPH/LUTS and increased risk of prostate cancer or addressed the subjective

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decisions of patients and/or surgeons to be treated for BPH/LITS (BPH-related medical or

surgical treatment was incorporated into our definition of progression BPH/LUTS). We did not

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apriori evaluate inflammation extent or intensity (except as a post-hoc analysis). As such,

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inflammation was dichotomized which may negatively affect the studys statistical power (we

did, however, describe a post-hoc analysis which showed a weak association between severity

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of chronic inflammation and incidence and progression of BPH/LUTS). We believe that the
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observations noted in this study are very likely real in this population of men, but they may not

be generalizable to a population of men who would not have been eligible to enroll in REDUCE
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trial (men who are not at risk to developing prostate cancer).

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The obvious strength of this analysis is that this is very likely the largest and longest
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longitudinal study evaluating the association between inflammation and BPH endpoints. The

study enrolled a population of men enriched with BPH (symptoms and prostate size) since the
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inclusion criteria favored larger prostates because of the generally higher PSA driving the
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decision to undergo the initial screening/baseline biopsy, while the screening biopsy itself
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ensured that there was not a high prevalence of undetected prostate cancer in the cohort.

Conclusion:

Men randomized to placebo treatment in the REDUCE study who were identified with

chronic prostate inflammation in the baseline biopsy, had greater LUTS and larger prostate

volumes than men without prostate inflammation had during the 4-year longitudinal study. The
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presence of prostate inflammation did not predict the progression of LUTS, development of

new BPH/LUTS, or progression of existing BPH/LUTS, but there was an association with more

severe inflammation. Chronic inflammation at baseline did predict increased prostate volume

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and AUR risk, over that same period.

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References
1. Nickel JC. Prostatic inflammation in benign prostatic hyperplasia - the third component? Can J Urol
1994;1:1.

2. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N

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Engl J Med 2010;362:1192.

3. Nickel JC, Roehrborn CG, O'Leary MP, et. al. The relationship between prostate inflammation and
lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol

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2008;54:1379.

4. Robert G, Descazeaud A, Nicolaew N, et al. Inflammation in benign prostatic hyperplasia: a 282

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patients immunohistochemical analysis. Prostate 2009;69:1774.

5. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and
combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med

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2003;349:2387.

6. Roehrborn CG, Kaplan SA, Noble WD, et al. The impact of acute or chronic inflammation in
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baseline biopsy on the risk of clinical progression of BPH: results fromthe MTOPS study. J Urol
2005;173:346.
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7. Tuncel A, Uzun B, Eruyar T, et. al. Do prostatic infarction, prostatic inflammation and prostate
morphology play a role in acute urinary retention? Eur Urol 2005;48:277.

8. Mishra VC, Allen DJ, Nicolaou C, et al. Does intraprostatic inflammation have a role in the
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pathogenesis and progression of benign prostatic hyperplasia? BJU Int 2007;100:327.

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9. Kwon YK, Choe MS, Seo KW, et al. The effect of intraprostatic chronic inflammation on benign
prostatic hyperplasia treatment. Korean J Urol 2010;51:266.

10. Nickel JC, True LD, Kreiger JN, et al. Consensus development of a histopathological classification
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system for chronic prostatic inflammation. BJUInt, 2001;87:797.

11. Nickel JC. Inflammation and benign prostatic hyperplasia. Urol Clin
North Am 2008;35:109.
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12. Gandaglia G, Briganti A, Gontero P et al. The role of chronic prostatic inflammation in the
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pathogenesis and progression of benign prostatic hyperplasia. BJUInt 2013;112:432

13. Kramer G,Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune
inflammatory disease? Eur Urol 2007;51:1202.
14. Untergasser G, Madersbacher S, Berger P. Benign prostatic hyperplasia: age-related tissue-
remodeling. Exp Gerontol 2005;40:121.
15. De Nunzio C, Aronson W, Freedland SJ, et al. The correlation between metabolic syndrome and
prostatic diseases. Eur Urol 2012;61:560.
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16. Gacci M, Vignozzi L, Sebastianelli A, et al. Metabolic syndrome and lower urinary tract symptoms:
the role of inflammation. Prostate Cancer Prostatic Dis 2013;16:101.

17. Roehrborn CG, Nickel JC, Andriole GL, et al. Dutasteride improves the outcomes of benign prostatic
hyperplasia when evaluated for prostate cancer risk reduction: a secondary analysis of the REduction by
DUtasteride of prostate Cancer Events (REDUCE) trial Urol 2011;78:641.

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Figure Legend:

Figure 1A: Median international prostate symptom score by acute inflammation

Figure 1B: Median international prostate symptom score by chronic inflammation

Figure 2A: Median prostate volume by acute inflammation

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Figure 2B: Median prostate volume by chronic inflammation

Figure 3A: Association of baseline acute prostate inflammation with BPH/LUTS-free survival in 797 men
who did not have history of baseline BPH/LUTS

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Figure 3B: Association of baseline chronic prostate inflammation with BPH/LUTS-free survival in 797
men who did not have history of baseline BPH/LUTS

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Figure 4A: Association of baseline acute prostate inflammation with BPH/LUTS progression-free survival
in 2659 men who had history of BPH/LUTS at baseline

Figure 4B: Association of baseline chronic prostate inflammation with BPH/LUTS progression-free

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survival in 2659 men who had history of BPH/LUTS at baseline
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Figure 5A: Cumulative incidence of AUR in the entire placebo group by baseline chronic inflammation

Figure 5B: Cumulative incidence of AUR in patients in the placebo group identified with BPH at baseline
by baseline chronic inflammation
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Supplemental Figure Legend

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Supplemental Figure 1: Mean international prostate symptom score by chronic inflammation severity
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Supplemental Figure 2A: Association of baseline chronic prostate inflammation with AUR-free survival
in the entire placebo group

Supplental Figure 2B: Association of baseline chronic prostate inflammation with AUR-free survival
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placebo treated subjects identified with BPH at baseline.

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Table 1: Baseline patient characteristics by baseline acute prostate inflammation

Acute inflammation
Characteristic P*
Absent Present
N (%) 3468 (84.4%) 641 (15.6%) --
Age (in years), mean (SD) 62.9 (6.1) 62.1 (6.2) 0.006
Race, N (%) 0.457

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White 3156 (91.0%) 577 (90.0%)
Other 311 (9.0%) 54 (10.0%)
BMI (in kg/m2), mean (SD) 27.4 (4.2) 27.4 (4.0) 0.901

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DRE, N (%) 0.721
Normal 3329 (96.2%) 611 (95.8%)
Abnormal

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133 (3.8%) 27 (4.2%)
PSA (in ng/mL), mean (SD) 5.9 (2.0) 5.7 (1.9) 0.009
PV (in cm3), mean (SD) 46.0 (18.3) 44.4 (21.1) 0.061
IPSS, mean (SD) 9.3 (5.7) 9.5 (6.0) 0.578

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Quality of life, mean (SD) 2.1 (1.4) 2.0 (1.3) 0.014
Peak flow (in mL/s), mean (SD) 14.7 (20.1) 14.7 (8.5) 0.940
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PVR (in mL), mean (SD) 47 (48) 44 (49) 0.246
BMI: body-mass index; DRE: digital rectal exam; IPSS: international prostate
symptom score; PSA: prostate-specific antigen; PV: prostate volume; PVR: post-
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void residual, SD: standard deviation.

*Chi-square test for categorical variables and Students t test for continuous
variables.
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Table 2: Baseline patient characteristics by baseline chronic prostate inflammation

Chronic inflammation
Characteristic P
Absent Present
N (%) 893 (21.7%) 3126 (78.3%) --
Age (in years), mean (SD) 62.3 (6.3) 62.9 (6.0) 0.011
Race, N (%) 0.012

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White 831 (93.1%) 2902 (90.3%)
Other 62 (6.9%) 313 (9.7%)
BMI (in kg/m2), mean (SD) 27.4 (3.8) 27.4 (4.3) 0.936

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DRE, N (%) 0.299
Normal 863 (96.7%) 3077 (95.9%)
Abnormal

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29 (3.3%) 131 (4.1%)
PSA (in ng/mL), mean (SD) 6.1 (2.0) 5.9 (2.0) 0.016
PV (in cm3), mean (SD) 43.3 (18.9) 46.5 (18.7) <0.001
IPSS, mean (SD) 8.8 (5.6) 9.5 (5.8) 0.001

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Quality of life, mean (SD) 2.0 (1.4) 2.1 (1.4) 0.031
Peak flow (in mL/s), mean (SD) 14.8 (7.5) 14.7 (21.7) 0.821
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PVR (in mL), mean (SD) 43 (47) 47 (48) 0.024
BMI: body-mass index; DRE: digital rectal exam; IPSS: international prostate
symptom score; PSA: prostate-specific antigen; PV: prostate volume; PVR: post-
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void residual, SD: standard deviation.

*Chi-square test for categorical variables and Students t test for continuous
variables.
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Table 3: Association of baseline prostate inflammation with development and progression of benign prostate hyperplasia

Development of BPH Progression of BPH symptoms

Baseline * *
Univariable Multivariable Univariable Multivariable
prostate
HR HR HR HR

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inflammation P P P P
(95%CI) (95%CI) (95%CI) (95%CI)
Acute 0.908 1.158 1.010 1.001
0.728 0.621 0.890 0.994

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(0.528-1.563) (0.648-2.067) (0.880-1.158) (0.868-1.154)

Chronic 0.754 0.672 0.966 0.953

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0.229 0.117 0.572 0.457
(0.477-1.194) (0.409-1.104) (0.857-1.089) (0.841-1.081)
BPH: benign prostate hyperplasia; HR: hazard ratio.
*Analyses controlled for baseline age, race, body-mass index, digital rectal exam, prostate volume, prostate-specific antigen, international

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prostate symptom score, quality of life, peak urinary flow, and post-void residual.

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Table 4: Association of baseline chronic prostate inflammation with acute urinary retention

Univariable Multivariable*
Sample HR HR

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P P
(95%CI) (95%CI)
All subjects 1.791 1.629
<0.001 0.004
(1.313-2.441) (1.173-2.263)

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Patients with
1.834 1.625
baseline <0.001 0.009
(1.305-2.577) (1.129-2.339)
BPH/LUTS

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BPH: benign prostate hyperplasia; LUTS: lower urinary tract
symptoms, HR: hazard ratio.
*Analyses controlled for baseline age, race, body-mass index, digital rectal exam, prostate
volume, prostate-specific antigen, international prostate symptom score, quality of life, peak

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urinary flow, and post-void residual.
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Supplemental Table 1: Association of baseline prostate inflammation with development of

BPH/LUTS (revised definition to include IPSS > 8)

Development of BPH/LUTS
Baseline
Univariable Multivariable*
prostate
HR HR
inflammation P P
(95%CI) (95%CI)

PT
Acute 1.010 0.908
0.889 0.605
(0.880-1.158) (0.630-1.309)

Chronic 1.068 1.021

0.674 0.903

RI
(0.786-1.451) (0.737-1.414)
BPH: benign prostate hyperplasia; LUTS: lower urinary tract
symptoms, HR: hazard ratio.

SC
*Analyses controlled for baseline age, race, body-mass index,
digital rectal exam, prostate volume, prostate-specific antigen,
international prostate symptom score, quality of life, peak

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urinary flow, and post-void residual. AN
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Supplemental table 2: Association of baseline chronic prostate inflammation severity with

development and progression of BPH/LUTS

Development of BPH/LUTS Progression of BPH symptoms

Baseline
Univariable Multivariable* Univariable Multivariable*
prostate
HR HR HR HR
inflammation P P P P
(95%CI) (95%CI) (95%CI) (95%CI)

PT
Chronic
None 1.0 1.0 1.0 1.0
n/a n/a n/a n/a
(reference) (reference) (reference) (reference)
Mild 0.807 0.702 0.980 0.953

RI
0.362 0.162 0.747 0.457
(0.509-1.280) (0.427-1.153) (0.868-1.107) (0.854-1.100)
Moderate or 0.754 0.189 0.852 0.797
0.052 0.032 0.128 0.044
Marked (0.057-1.010) (0.041-0.867) (0.692-1.047) (0.640-0.994)

SC
BPH: benign prostate hyperplasia; LUTS: lower urinary tract
symptoms, HR: hazard ratio.
*Analyses controlled for baseline age, race, body-mass index, digital rectal exam, prostate
volume, prostate-specific antigen, international prostate symptom score, quality of life, peak

U
urinary flow, and post-void residual.
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Key of Abbreviations

BPE benign prostatic enlargement

BPH benign prostatic hyperplasia
IPSS International Prostate Symptom Score
LUTS lower urinary tract symptoms
PSA prostate specific antigen

PT
REDUCE REduction by DUtasteride of prostate Cancer Events (REDUCE)
trial

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