Chemokines may predict response to neuromodulation

Royal Oak, MI-Urinary measurement of inflammatory chemokines may offer a noninvasive method for evaluating treatment response to sacral neuromodulation (InterStim Therapy, Medtronic, Inc., Minneapolis) in patients with interstitial cystitis/painful bladder syndrome (IC/PBS), says Michael Chancellor, MD.

Dr. Chancellor reported the results of a study showing changes in urinary levels of various chemokines 24 weeks after patients began treatment with sacral neuromodulation and correlations between some changes and improvements in bladder diary and symptom score data.

“Sacral neuromodulation has been demonstrated to be beneficial in patients with IC/PBS. However, assessment of the effect is symptom-based, and the availability of an objective biomarker of treatment response would be desirable,” said Dr. Chancellor, professor and director of neurourology at Oakland University William Beaumont School of Medicine, Royal Oak, MI.

“Our early data suggest urinary inflammatory chemokines may be a downstream effector of neuromodulation response in the bladder. A larger study is needed to establish whether urine chemokine measurement might have a role for guiding us on the use of neuromodulation of patients with IC/PBS and to predict treatment response,” added Dr. Chancellor, who presented the findings at the AUA annual meeting in San Diego.

Patients enrolled in the study had a confirmed diagnosis and long history of IC/PBS. At baseline and 24 weeks after neuromodulation, they completed the O’Leary-Sant IC Symptom and Problem Indices (ICSPI) and provided midstream urine samples that were analyzed for a panel of pro- and anti-inflammatory chemokines using a microsphere-based array (Luminex xMAP analysis). Senior author Kenneth M. Peters, MD, treated the patients.

Baseline data were available from 16 patients and showed statistically significant positive correlations between number of daily voids and both NCP-1 and CXCL-1 and between the total ICSPI score and levels of sIL-1ra and CXCL-1.

Symptoms, chemokine levels decrease

Analyses of data from seven patients with complete follow-up after 24 weeks showed a significant decrease in median ICSPI from 28 to 14 and in urinary levels of sIL-1ra and MCP-1. Levels of CXCL-1, CXCL-10, CCL5 (RANTES), IL-8, VEGF, and PDGF were also decreased compared with pretreatment, although the differences did not achieve statistical significance due to variability in the data.

Lower chemokine levels correlated negatively with the ICSPI score at 24 weeks, although the relationship did not achieve statistical significance. Multivariable analysis of the data revealed that sIL-1ra and MCP-1 together explained the majority of variance in data, Dr. Chancellor reported.

Dr. Chancellor noted that although follow-up data in this investigation were collected after 24 weeks, studies in animals with experimentally induced cystitis show that changes in urinary chemokines occur fairly soon after initiating neuromodulation therapy.

“Animal studies have the advantage of enabling complete serial urine collection. However, it is hard to extrapolate the animal findings to humans,” he said.

Dr. Chancellor explained that several lines of evidence provided a rationale for investigating urinary chemokines as a marker of response to neuromodulation in patients with IC/PBS. Results of an animal study showed significant temporal changes in urinary chemokine levels after induction of cystitis by intraperitoneal cyclophosphamide administration, and it has been reported that levels of MCP-1 in the urine and bladder tissue are increased in patients with ulcerative cystitis. Additionally, it is known that neuromodulation affects opioid receptors and that these receptors are suppressed by chemokines that increase pain.

Dr. Chancellor is an investigator for and has received grant support from Medtronic, and Dr. Peters is a consultant/adviser for the company.UT

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