Observational Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Urol. Mar 24, 2017; 6(1): 18-26
Published online Mar 24, 2017. doi: 10.5410/wjcu.v6.i1.18
Urine chemokine levels correlate with treatment response to phosphodiesterase 4 inhibitor in prostatitis
Pradeep Tyagi, Kim Killinger, Gregory McLennan, Nirmal Jayabalan, Michael Chancellor, Kenneth M Peters
Pradeep Tyagi, Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
Kim Killinger, Gregory McLennan, Michael Chancellor, Kenneth M Peters, Oakland University William Beaumont School of Medicine, Beaumont Hospital-Royal Oak, Oakland, MI 48073, United States
Nirmal Jayabalan, School of Material Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore
Author contributions: All the authors contributed to the manuscript.
Institutional review board statement: The study was reviewed and approved by the Human Investigation Committed of Oakland University William Beaumont School of Medicine.
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: None of the authors other than Kenneth Peters have a conflict; Dr. Kenneth M Peters was the investigator of Celgene Sponsored Clinical Trial.
Data sharing statement: No data were created no data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Pradeep Tyagi, PhD, Associate Professor, Department of Urology, University of Pittsburgh School of Medicine, Suite 700 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, United States. tyagip@upmc.edu
Telephone: +1-412-6924119 Fax: +1-412-6924380
Received: August 12, 2016
Peer-review started: August 16, 2016
First decision: September 28, 2016
Revised: October 27, 2016
Accepted: December 13, 2016
Article in press: December 15, 2016
Published online: March 24, 2017
Processing time: 202 Days and 14.5 Hours
Abstract
AIM

To investigate the association of urinary chemokines with the treatment response in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) patients.

METHODS

Between 2007-2011, 18 out of 21 male CP/CPPS patients met the exclusion/inclusion criteria of the 16 wk longitudinal study on twice daily oral treatment with Phosphodiesterase 4 inhibitor called Apremilast for 12 wk. Symptom scores and urine specimen were collected at baseline and every visit at 4 wk interval from CP/CPPS patients who completed at least 8 wk of drug treatment. Urine collected at each visit was frozen and then analyzed together after thawing for chemokines and growth factors using MILLIPLEX™ MAP immunoassay. Cross sectional association of Chronic Prostatitis Symptom Index (CPSI) and visual analog scale (VAS) with chemokine levels in urine collected at baseline was assessed in 18 CP/CPPS patients relative to 10 asymptomatic male subjects. Longitudinal association between urine chemokine levels and symptom scores was assessed in 8 treatment-adherent CP/CPPS patients at baseline and at 4, 8, 12 and 16 wk.

RESULTS

Urine chemokines levels of CXCL-1 (GRO-a), CXCL-8 (IL-8), CXCL-10 (IP-10) and CCL5 (RANTES) in CP/CPPS patients at baseline were significantly elevated relative to asymptomatic subjects, whereas levels of sIL-1RA in CP/CPPS were significantly lower compared to controls (P < 0.05). Quantitatively, urine levels of CXCL-10 were higher than other chemokines in CP/CPPS, but its 5 fold change relative to controls was lower than the 20 fold change noted for CXCL-8. The mean age of enrolled patients who completed at least 8 wk of treatment (n = 8) was 46.5 ± 9.4 years and analysis found that elevation of CXCL-8 and CCL5 increased the odds for higher score of CPSI by 54% and 25%, respectively (F test, P = 0.00007). Urine levels of CCL2 (MCP-1) and CXCL-10 together explained approximately 85% of variance in longitudinal data on multivariate analysis. Bivariate analysis of 5 patients who fully complied and completed the assigned dose regimen, showed strong linear correlation of reduced urine levels of CXCL-10, CXCL-8, CCL5, CCL2 and PDGF with improvement in clinical activity as measured by pain VAS and CPSI (Pearson r = 0.83-0.97; P < 0.05).

CONCLUSION

Urine levels of CXCL-10, CCL2 and PDGF can be sensitive, objective and non-invasive markers of response to new therapeutic intervention in CP/CPPS patients.

Keywords: Chronic prostatitis; Longitudinal measurement; Phosphodiesterase 4; Urine; Chronic pelvic pain syndrome; Chemokines

Core tip: Chronic prostatitis or chronic pelvic pain syndrome is a poorly understood and prevalent male condition, which is generally described by pelvic pain in the absence of demonstrable urinary or genital tract infection. Inflammation is considered to play a critical role in the prostatitis and so we carried out a small physician initiated clinical study to investigate the potential efficacy of a new phosphodiesterase 4 inhibitor drug, Apremilast. Urine was collected from the study participants at the baseline and at each visit to assay the chemokine levels and then determine their association with the treatment response. We are the first to report that chemokine levels in urine instead of the semen or prostatic secretions have the potential to serve as non-invasive biomarkers of severity and treatment response of the prostatitis patients.