Improves Symptoms and Urinary Biomarkers in Refractory Interstitial Cystitis/Bladder Pain Syndrome Patients Randomized to Extracorporeal Shock Wave Therapy Versus Placebo

doi:10.21203/rs.3.rs-111102/v1

Extracorporeal shock wave therapy (ESWT) has been shown to improve symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS); however, there is a lack of objective evidence. We measured change of urinary biomarker levels in 25 patients with IC/BPS received ESWT or placebo once a week for 4 weeks. Urines were collected from participants at baseline, 4 and 12 weeks post treatment. A representative 41 inflammatory growth factors, cytokines, and chemokines in urine were measured using a MILLIPLEX immunoassay kit. Symptom bother was assessed by O’Leary-Sant symptom scores (OSS), and visual analog scale (VAS) for pain.

The ESWT group exhibited a significant reduction in the OSS and VAS compared to the placebo group 4 weeks post-treatment (p < 0.05), and the effects were persistent at 12 weeks. The difference in urinary markers change in ESWT vs placebo was p= 0.054 for IL4, p=0.013 for VEGF, and p= 0.039 for IL9 at 4 weeks. The change of urine biomarker was not significant in other biomarkers or all the measured proteins at 12 weeks. The current data suggest that IL4, IL9, and VEGF mediation may be involved in its pathophysiologic mechanisms and response to LESW treatment.

Urology & Nephrology

Bladder Pain Syndrome

Interstitial Cystitis

Shock Wave

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease characterized by symptoms of unpleasant sensation, pain, pressure, and discomfort perceived to be related to the urinary bladder, associated with lower urinary tract symptoms, in the absence of infection or other identifiable causes.¹ Treatment of refractory IC/BPS patients includes hydrodistension, oral medications, and intravesical therapy has met with only limited efficacy and there is an unmet need for developing new therapy for IC/BPS.²

The etiology and pathogenesis of IC/BPS are multifactorial and several studies have attributed to the exhibited symptoms to an increase in inflammatory cells infiltration, hypoxia-inducible factor-1α, VEGF, and apoptosis^3,4 noted on histopathological and molecular studies. Thus, the treatment of IC/BPS aiming at regulation of inflammatory reaction and regeneration or repair of urothelium defect could be an attractive option for the management of refractory IC/BPS.

Low energy shock wave (LESW), known to exert anti-inflammatory, anti- apoptotic effects, and improve tissue repair, has been applied for the treatment of urological disease, including erectile dysfunction, and chronic prostatitis chronic pelvic pain syndrome.^{5, 6} Furthermore, recent publications have been extended into the field of bladder dysfunction and demonstrated therapeutic effects of LESW on overactive bladder and IC/BPS.^{7, 8} The approaches used for mechanistic studies on efficacy of LESW in animal model^6,9 need to be modified for human confirmation . Towards that end we assessed the change in urine levels of multiple growth factors, cytokines, chemokines, and clinical symptoms of IC/BPS patients at baseline and after LESW or placebo treatment.

Study Design

The Urinary Marker study was a planned exploratory supplementary study to the Low Energy Shock Wave (LESW) for the treatment of IC/BPS — a multicenter, randomized, double-blind, placebo-controlled, prospective study

(ClinicalTrials.gov number, NCT03619486). Details of the trial design and methods have been previously published.⁸

The current study only included patient population from one center for urinary marker analysis. The IC/BPS confirmed patients were randomly assigned to receive (1) LESW or (2) placebo group in a 1:1 ratio after the review and approval by the Institutional Review Board of the hospital (Chang Gung Memorial Hospital IRB 201800525A3), and was in compliance with the ethical principles of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Informed consent was obtained from patients before any study procedures were performed.

Study Population

Patients with IC/BPS, who aged 20 years or above and had failed at least 6 months of conventional treatments, were enrolled. The diagnosis of IC/BPS was established based on characteristic symptoms and cystoscopic findings of glomerulations, petechia, or mucosal fissures upon hydrodistention. The inclusion and exclusion criteria are listed in the Appendix of our previous publication.⁸

Treatment

The procedures were done as an office procedure without any anesthesia. Studied patients were placed in a supine position with bladder distended with up to 50 to 100 cc of urine volume as detected by transabdominal ultrasonography. The shock wave applicator (LITEMED LM ESWT mini system, Taiwan) or placebo applicator were gently placed directly on the ultrasound transmission gel over the skin surface of suprapubic region above the urinary bladder once a week for 4 weeks, with 2000 shocks, frequency of 3 pulses per second, and maximum energy flow density 0.25 mJ/mm².⁸ Follow-up visits were scheduled at one week, four weeks, and three months post-treatment.

Urine Processing

Urine samples were collected at baseline, post treatment 4 weeks and 12 weeks at KCGMH. Specimens were kept on ice or at 4° C for short times until stored at −80° C (within 2-4 hrs). The urine was centrifuged (12000rpmx 15 mins) at 4° C, and the supernatants were directly analyzed.

Multiplex Analysis

The urine sample were stored at -80°C until analysis by MILLIPLEX MAP Human Cytokine/Chemokine Panel (Merck Millipore, Billerica, MA), a magnetic bead-based immunology multiplex assay, which can simultaneously quantify the following 41 human cytokines: sCD40L, EGF, FGF-2, Flt-3 ligand, Fractalkine, G-CSF, GM-CSF, GRO, IFN-α2, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IP-10, MCP-1, MCP-3, MDC (CCL22), MIP-1α, MIP-1β, PDGF-AB/BB, RANTES, TGF-α, TNF-α, TNF-β, VEGF, Eotaxin/CCL11, PDGF-AA. The samples were processed in duplicate according to the manufacturer’s instructions.¹⁰ Cytokine concentrations were normalized to urine creatinine content.

Outcome Measures

The average changes in O’Leary-Sant symptom scores (OSS), a 3-day voiding diary, Visual Analog Pain Scale (VAS, 0–10), global response assessment (GRA) with categorizations (-3, -2, -1, 0, 1, 2, 3), uroflowmetry, and residual urine detected by ultrasonography at 1, 4, and 12 weeks were compared to baseline and between groups after treatment.

Statistical Methods

The average change in values from baseline at 1, 4, and 12 weeks post-treatment in studied parameters, scores or outcome measures, and net changes of each efficacy item between treatment group and the controlled groups were analyzed using generalized estimating equation. The patient-responded global assessment was analyzed using Fisher’s exact test between the treatment and the controlled groups. All statistical assessments were considered significant at P<0.05. Statistical analyses were performed using SPSS version 22.0 statistical software (SPSS Inc., Chicago, IL).

Patient disposition

A total of 27 patients were screened and 25 eligible patients were randomly allocated into two subgroups. One patient withdrew consent and thereby did not receive any treatment (Fig. 1). The final intent-to-treat population consisted of 24 subjects, including 13 in ESWT, and 11 in placebo groups of whom all subjects completed the primary endpoint evaluation (i.e. four weeks post-treatment). The baseline characteristics were comparable across the treatment groups except pain and voided volume, which was significant less in the placebo group (Table 1 and 2). None of the participants had Hunner lesions, but all of them showed some evidence of bladder inflammation from pathological findings.

Efficacy and Safety

Statistically significant improvements occurred in the pain scale and OSS, including ICSI and ICPI, from baseline to 1 week, 4 weeks and 12 weeks after treatment in ESWT group (Table 2; Fig.2) compared to an insignificant change in the placebo group for OSS, ICSI, ICPI, and VAS. The difference in improvement between ESWT vs placebo for OSS was -5.4 (-8.3,- 2.5) vs -0.9 (-4.0, 2.2) (95% CI; p= 0.014) at 4 weeks and the efficacy was maintained till 12 weeks (Fig. 2). The difference in VAS improvement was-2.0 (-3.1, -0.9) vs -0.6 (-1.4, 0.3) (95% CI; p= 0.018) at 4 weeks, and the efficacy lasted till 12 weeks. No patient had urinary incontinence, retention or infection with ESWT or placebo treatment.

Urine biomarkers

Of the 41 candidate markers, 19 markers were measurable in urine and analyzed. Biomarkers levels at baseline, 4 and 12 weeks following treatment are shown in Table 3. No baseline differences were found between ESWT and placebo groups. IL4, IFNα2, and VEGF levels were significantly increased at 4 weeks in placebo group, and IL9, and Flt3 levels were significantly increased at 4 weeks post ESWT treatment. The difference between ESWT vs placebo for the change in urinary markers was -0.0 (-0.3, 0.2) vs 0.4 (-0.0, 0.9) (95% CI; IL4, p= 0.054) and -0.5 (-1.3, 0.7) vs 1.2 (0.3, 2.1) (95% CI; VEGF, p=0.013), and 0.2 (-0.0, 0.4) vs -0.0 (-0.1, 0.0) (95% CI; IL9, p= 0.039) at 4 weeks (Table.4).

Similar to previous reports, ESWT was associated with a statistically significant decrease in OSS and VAS pain scale at 4 weeks post-treatment with lower intensity of placebo effect. In contrast to the previous report from our group,⁸ placebo group has no statistically significant change in OSS and VAS pain scale at 4 weeks post-treatment, which is reflected in the detection of significant difference in symptomatic improvement between ESWT vs placebo that eluded us in previous study. The lower intensity of placebo effect in this study may be due to a more homogenous patient population in a single study center.

The main goal of the current study was to identify changes in urine biomarkers pre and post-treatment and investigation to the mechanistic understanding of ESWT efficacy on IC/BPS. It has been known that ischemia/hypoxia condition occurs in the bladder mucosa and contributes to IC/BPS symptoms.¹¹ VEGF is a signal protein that stimulates the formation of blood vessels to restore the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions. Bladder urothelium of IC/BPS patients has been shown to exhibit significantly higher expressions of VEGF, which then induces bladder fibrosis and reduces bladder capacity after chronic inflammation.¹¹ Furthermore, VEGF expression level was associated with the grade of bladder pain.¹² A previous study showed that intravesical botulinum toxin A injection reduced the expression of VEGF associated with a concomitant decrease in inflammatory marker levels in patients with IC/BPS.¹³ Anti-vascular endothelial growth factor treatment has been demonstrated to decrease bladder pain in animal model of cyclophosphamide cystitis.¹⁴ In the present study, urine VEGF level was significantly increased at 4 weeks follow-up in placebo group. However, the ESWT group showed a reduction of VEGF expressions at 4 weeks. Our study suggests that ESWT has the potential to decrease urinary VEGF expression and alleviate IC/BPS symptoms.

Sugaya et al. have reported that about 35% of the patients with interstitial cystitis had some type of allergic or autoimmune disease,¹⁵ which is associated with overproduction of IL-4. IC/BPS is characterized by an increased number of mast cells in the detrusor and release of cytokines, including IL-4.¹⁶ Another study from rat model demonstrated that intravesical HCl induced an increase of mast cells in the bladder, and ESWT can induce a decrease of mast cells and alleviate the HCl induced inflammatory effects.¹⁷ Our current results showed that IL-4 was significantly increased at 4 weeks in the placebo group, whose increase was suppressed by ESWT. We suggested that ESWT might have effects on immune modulation through mast cells IL4 reaction.

IL-9 is a cytokine secreted by CD4+ helper cells that regulates a variety of hematopoietic cells, including stimulation of cell proliferation and prevention of apoptosis.¹⁸ The current results showed that urinary IL-9 is increased in ESWT group, which was not observed in the placebo group at 4 weeks. This finding might indicate an immune modulation effect of ESWT on IC/BPS patients.

The limitation of this study is the lack of a non-IC/BPS control arm and small sample size. Further control study with larger sample size is necessary to elucidate the actual therapeutic efficacy and urine biomarker change of ESWT.

In conclusion, our clinical study demonstrated that compared to placebo, ESWT in IC/BPS patients improved OSS and pain scale in association with some urine cytokine and chemokine changes. Further study with large patient number is necessary to elucidate the real role of ESWT on urinary biomarker changes.

Acknowledgement:

We appreciate Chang Chien Pei-Wen, and the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistics work.

Author Contributions

Y-C.S. W-C.L. Y-C.C designed the study and all authors interpreted the data and prepared the manuscript and reviewed the manuscript.

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Table 1. Baseline patient characteristics

Variable	Placebo (n=12)	ESWT (n=13)
Variable	Mean (95%CI)	Mean (95%CI)	p value^a
Age	57.8 (49.5, 66.0)	55.7 (48.3, 63.1)	0.687
No. Male/Female	5/6	3/10	0.340
Max bladder capacity (ml)^b	618.6 (521.0, 716.2)	677.0 (595.6, 758.4)	0.322
Duration of disease (yr)	5.8 (4.2, 7.3)	6.2 (3.6, 8.8)	0.758

Values are presented as mean (95%CI).

*: P < 0.05, **: P < 0.01, ***: P < 0.005, ****: P < 0.0001

^a: Comparison between ESWT and placebo (Two sample t-test).

^b: During hydrodistention.

Table 2. Variables at baseline, 1, 4, and 12 weeks in patients in ESWT and placebo

Variable	Placebo (N=12)		ESWT (N=13)
Variable	Mean (95% CI)	p value ^a	Mean (95% CI)	p value ^a	p value^b
O' Leary-Sant score
Baseline	25.6 (22.5, 28.6)		26.0 (22.6, 29.4)		0.834
Wk 1	23.6 (19.8, 27.3)	0.061	20.4 (16.9, 23.9)	**** < 0.0001
Wk 4	24.8 (21.3, 28.3)	0.512	20.6 (16.6, 24.6)	**** < 0.0001
Wk 12	25.1 (20.7, 29.6)	0.061	18.2 (13.2, 23.1)	**** < 0.0001
ICSI
Baseline	12.3 (10.1, 14.5)		12.7 (10.6, 14.8)		0.789
Wk 1	10.8 (8.1, 13.6)	0.056	9.3 (7.1, 11.5)	*** 0.001
Wk 4	11.7 (8.9, 14.6)	0.511	9.2 (6.9, 11.5)	**** < 0.0001
Wk 12	11.8 (8.4, 15.2)	0.958	7.9 (5.0, 10.9)	**** < 0.0001
ICPI
Baseline	13.3 (11.5, 15.0)		13.3 (11.8, 14.8)		0.954
Wk 1	12.7 (11.1, 14.4)	0.518	11.1 (9.4, 12.7)	*** 0.001
Wk 4	13.1 (11.8, 14.4)	0.795	11.2 (9.4, 13.1)	*** 0.001
Wk 12	13.3 (11.5, 15.1)	0.567	10.2 (8.0, 12.5)	*** 0.001
VAS
Baseline	5.3 (4.2, 6.3)		6.9 (5.8, 8.0)		* 0.017
Wk 1	5.1 (4.0, 6.2)	0.513	4.9 (3.4, 6.3)	**** < 0.0001
Wk 4	4.8 (4.0, 6.1)	0.192	4.9 (3.3, 6.4)	**** < 0.0001
Wk 12	5.2 (3.1, 7.3)	0.862	4.7 (3.0, 6.4)	**** < 0.0001
FBC (ml)
Baseline	282.1 (197.3, 366.8)		315.4 (258.0, 372.8)		0.456
Wk 1)	238.9 (163.5, 314.3)	* 0.037	287.7 (231.9, 343.5)	0.161
Wk 4	294.6 (194.9, 394.2)	0.381	296.9 (225.8, 368.0)	0.359
Wk 12	250.6 (142.0, 359.2)	0.222	293.2 (218.5, 367.8)	0.177
Frequency
Baseline	11.6 (7.7, 15.5)		11.1 (8.8, 13.4)		0.793
Wk 1	12.4 (9.0, 15.8)	0.376	10.2 (7.7, 12.7)	0.088
Wk 4	12.0 (8.5, 15.8)	0.908	10.4 (7.2, 13.6)	0.331
Wk 12	12.6 (7.2, 18.1)	* 0.022	9.8 (6.7, 13.0)	** 0.005
Nocturia
Baseline	2.6 (1.4, 3.8)		1.7 (0.7, 2.8)		0.196
Wk 1	2.9 (1.5, 4.3)	0.243	1.7 (0.7, 2.6)	0.792
Wk 4	2.3 (1.0, 3.6)	0.380	1.6 (0.6, 2.7)	0.780
Wk 12	3.9 (1.4, 6.4)	0.125	1.8 (0.7, 0.9)	0.889
Qmax (ml/s)
Baseline	14.4 (8.5, 20.2)		16.3 (12.0, 20.7)		0.533
Wk 1	17.5 (9.9, 25.2)	0.373	16.8 (13.4, 20.3)	0.663
Wk 4 (N=11, 13)	17.6 (10.5, 24.6)	0.329	17.1 (11.9, 22.4)	0.705
Wk 12 (N=8, 11)	21.1 (11.5, 30.6)	0.290	16.0 (12.9, 19.1)	0.873
Voided Volume (ml)
Baseline	172.0 (112.1, 231.8)		256.9 (187.5, 326.4)		* 0.034
Wk 1	185.0 (129.2, 240.8)	0.835	277.0 (199.4, 354.6)	0.316
Wk 4	238.6 (150.0, 327.1)	0.075	248.8 (163.4, 334.3)	0.792
Wk 12	243.1 (177.2, 308.9)	0.106	320.6 (210.8, 430.4)	* 0.038
Residual Urine (ml)
Baseline	25.0 (7.7, 42.4)		33.8 (17.0, 50.5)		0.408
Wk 1	32.1 (10.6, 53.6)	0.680	25.5 (15.7, 35.2)	0.303
Wk 4	31.7 (9.1, 54.4)	0.415	28.8 (5.6, 51.9)	0.409
Wk 12	31.3 (6.1, 56.5)	0.590	38.5 (13.7, 63.3)	0.748
GRA (<2/≥2)
Wk 1	9/2 (18.2%)		6/7 (53.8%)		0.105^c
Wk 4	8/3 (27.3%)		6/7 (53.8%)		0.240^c
Wk 12	8/1 (11.1%)		6/7 (53.8%)		0.074^c

Values are presented as mean (95% CI).

*: P < 0.05, **: P < 0.01, ***: P < 0.005, ****: P < 0.0001

^a: Generalized estimating equation compared with baseline.

^b: Comparison between corresponding time point of ESWT and placebo (Generalized estimating equation).

^c: Comparison between corresponding time point of ESWT and placebo (Fisher's Exact Test).

Table 3. Cytokine at baseline, 1, 4, and 12 weeks in patients in ESWT and placebo

Cytokine (pg/mg of Creatinine)	Placebo (N=11)		ESWT (N=13)
Cytokine (pg/mg of Creatinine)	Mean (95% CI)	p value ^a	Mean (95% CI)	p value ^a	p value^b
IL-1RA
Baseline	7.9 (0.1, 15.7)		14.8 (-4.2, 33.9)		0.493
Wk 1	5.3 (1.1, 9.5)	0.685	35.4 (-26.2, 96.9)	0.305
Wk 4	8.6 (2.7, 14.5)	0.921	19.0 (-3.3, 41.3)	0.936
Wk 12	20.4 (-14.7, 55.5)	* 0.015	40.7 (-35.7, 117.0)	0.141
IL-4
Baseline	0.5 (0.0, 1.0)		0.5 (0.1, 0.9)		0.972
Wk 1	0.5 (0.0, 1.1)	0.629	0.3 (0.1, 0.5)	0.301
Wk 4	0.9 (0.1, 1.7)	* 0.028	0.5 (0.1, 1.0)	0.776
Wk 12	0.8 (-0.2, 1.7)	0.760	0.9 (0.2, 1.6)	**** < 0.0001
IL-6
Baseline	0.2 (0.1, 0.2)		0.2 (0.1, 0.2)		0.685
Wk 1	0.2 (0.1, 0.3)	0.834	0.2 (0.1, 0.4)	0.241
Wk 4	0.3 (-0.1, 0.7)	0.214	0.2 (0.1, 0.3)	0.746
Wk 12	0.1 (0.0, 0.3)	0.462	0.2 (0.2, 0.3)	0.168
IL-8
Baseline	1.3 (-0.4, 2.9)		1.1 (-0.1, 2.2)		0.812
Wk 1	0.3 (0.1, 0.4)	0.775	2.8 (-1.0, 6.6)	* 0.035
Wk 4	4.9 (-4.5, 14.2)	0.302	1.3 (-0.2, 2.8)	0.970
Wk 12	1.3 (-1.1, 3.7)	0.988	1.5 (-1.0, 4.0)	0.928
IL-9
Baseline	0.2 (0.1, 0.3)		0.4 (0.2, 0.5)		0.179
Wk 1	0.2 (0.1, 0.3)	0.255	0.5 (0.2, 0.7)	** 0.005
Wk 4	0.2 (0.2, 0.2)	0.322	0.5 (0.3, 0.8)	*** 0.002
Wk 12	0.2 (0.0, 0.3)	0.070	0.4 (0.3, 0.5)	0.478
IL-10
Baseline	0.3 (0.1, 0.4)		0.3 (0.2, 0.4)		0.864
Wk 1	0.3 (0.1, 0.4)	0.930	0.3 (0.1, 0.5)	0.572
Wk 4	0.3 (0.2, 0.4)	0.221	0.3 (0.2, 0.5)	0.557
Wk 12	0.3 (0.0, 0.6)	0.896	0.5 (0.3, 0.7)	*** 0.003
IL-15
Baseline	0.3 (0.2, 0.5)		0.3 (0.2, 0.4)		0.928
Wk 1	0.3 (0.2, 0.5)	0.902	0.4 (0.2, 0.5)	0.722
Wk 4	0.4 (0.2, 0.5)	0.543	0.4 (0.2, 0.6)	0.345
Wk 12	0.3 (0.1, 0.6)	0.402	0.5 (0.3, 0.8)	*** 0.003
FGF2
Baseline	3.7 (0.7, 6.8)		3.7 (1.6, 5.7)		0.956
Wk 1	2.5 (1.4, 3.7)	0.126	4.6 (1.6, 7.7)	0.556
Wk 4	4.3 (2.6, 6.0)	0.275	4.0 (1.8, 6.2)	0.909
Wk 12	3.3 (0.7, 5.9)	0.476	5.7 (2.2, 9.1)	0.091
G-CSF
Baseline	0.8 (0.4, 1.2)		1.0 (0.2, 1.7)		0.781
Wk 1	0.7 (0.2, 1.2)	0.467	0.8 (0.4, 1.2)	0.710
Wk 4	1.7 (0.3, 3.1)	0.061	1.3 (0.2, 2.4)	0.398
Wk 12	0.9 (0.1, 1.8)	0.193	1.5 (0.7, 2.3)	0.094
Flt3
Baseline	0.8 (0.4, 1.3)		0.8 (0.3, 1.3)		0.963
Wk 1	0.9 (0.4, 1.5)	0.635	0.9 (0.4, 1.3)	0.224
Wk 4	1.0 (0.3, 1.6)	0.355	1.0 (0.4, 1.6)	**** < 0.0001
Wk 12	1.3 (0.3, 2.3)	0.313	1.0 (0.4, 1.6)	**0.005
Fractalkine
Baseline	8.1 (2.8, 13.4)		7.0 (3.3, 10.7)		0.708
Wk 1	7.9 (4.3, 11.6)	0.705	6.9 (2.5, 11.2)	0.946
Wk 4	10.0 (5.2, 14.7)	0.316	6.1 (3.3, 8.9)	0.647
Wk 12	6.6 (-0.1, 13.3)	0.115	8.4 (4.1, 12.7)	0.391
IFNα2
Baseline	0.9 (0.3, 1.5)		1.2 (0.5, 2.0)		0.512
Wk 1	0.7 (0.4, 1.1)	0.678	1.1 (0.4, 1.8)	0.835
Wk 4	1.7 (0.7, 2.7)	* 0.046	1.0 (0.5, 1.4)	0.608
Wk 12	0.9 (0.1, 1.8)	0.561	1.4 (0.6, 2.1)	0.475
GRO
Baseline	1.2 (0.3, 2.0)		0.9 (0.4, 1.5)		0.595
Wk 1	0.8 (0.3, 1.4)	0.233	0.8 (0.3, 1.4)	0.842
Wk 4	1.7 (0.2, 3.2)	0.183	1.4 (0.1, 2.7)	0.214
Wk 12	1.4 (0.1, 2.6)	0.051	1.5 (0.6, 2.4)	0.156
MCP-1
Baseline	23.6 (11.3, 36.0)		26.1 (15.2, 36.9)		0.744
Wk 1	26.1 (11.7, 40.4)	0.693	28.4 (8.4, 48.3)	0.726
Wk 4	18.1 (11.6, 24.6)	0.216	30.2 (9.6, 50.7)	0.569
Wk 12	16.8 (3.4, 30.3)	0.718	25.1 (14.1, 36.1)	0.978
MCP-3
Baseline	1.3 (0.4, 2.2)		1.3 (0.7, 2.0)		0.873
Wk 1	1.0 (0.6, 1.4)	0.432	1.4 (0.6, 2.3)	0.864
Wk 4	1.6 (1.0, 2.1)	0.125	1.4 (0.7, 2.2)	0.823
Wk 12	1.3 (0.3, 2.3)	0.662	2.1 (0.9, 3.2)	* 0.033
VEGF
Baseline	1.1 (0.5, 1.7)		1.5 (0.6, 2.3)		0.429
Wk 1	1.5 (0.7, 2.4)	0.519	1.1 (0.7, 1.5)	0.413
Wk 4	2.3 (1.1, 3.4)	*** 0.004	1.2 (0.4, 2.0)	0.276
Wk 12	1.6 (0.4, 2.9)	0.960	1.8 (0.9, 2.6)	0.231
Eotaxin
Baseline	0.8 (0.4, 1.3)		0.9 (0.6, 1.3)		0.694
Wk 1	0.9 (0.2, 1.5)	0.958	0.9 (0.5, 1.4)	0.990
Wk 4	1.1 (0.8, 1.4)	0.464	1.1 (0.7, 1.6)	0.421
Wk 12	1.0 (0.1, 1.9)	0.829	1.4 (0.9, 1.9)	**** < 0.0001
RANTES
Baseline	0.6 (0.3, 0.9)		0.7 (0.3, 1.1)		0.619
Wk 1	0.7 (0.3, 1.0)	0.980	0.5 (0.3, 0.7)	0.322
Wk 4	5.4 (-4.9, 15.7)	0.176	0.8 (0.4, 1.2)	0.471
Wk 12	0.7 (0.1, 1.4)	0.937	0.9 (0.5, 1.2)	0.624
TNF-β
Baseline	0.2 (0.1, 0.3)		0.2 (0.1, 0.3)		0.921
Wk 1	0.1 (0.1, 0.2)	0.532	0.2 (0.1, 0.4)	0.529
Wk 4	0.2 (0.1, 0.3)	0.504	0.2 (0.1, 0.4)	0.544
Wk 12	0.2 (0.0, 0.3)	0.543	0.3 (0.2, 0.4)	0.105

Values are presented as mean (95% CI).

*: P < 0.05, **: P < 0.01, ***: P < 0.005, ****: P < 0.0001

^a: Generalized estimating equation compared with baseline.

^b: Comparison between corresponding time point of ESWT and placebo (Generalized estimating equation).

^c: Comparison between corresponding time point of ESWT and placebo (Fisher's Exact Test).

Table 4. Cytokines at post-treatment 1, 4, and 12 weeks in patients in ESWT and placebo

Cytokine (pg/mg of Creatinine)	Placebo (N=11)		ESWT (N=13)
Cytokine (pg/mg of Creatinine)	Mean (95% CI)	p value ^a	Mean (95% CI)	p value ^a	p value^b
IL-1RA
Wk 1	-4.3 (-12.0, 3.5)	0.424	20.6 (-22.1, 63.2)	1.000	0.298
Wk 4	0.7 (-5.3, 6.6)	0.898	3.4 (-2.3, 9.1)	1.000	0.458
Wk 12	9.8 (-12.8, 32.4)	0.079	24.8 (-28.6, 78.2)	1.000	0.632
IL-4
Wk 1	-0.1 (-0.7, 0.6)	0.772	-0.2 (-0.6, 0.1)	0.138	0.577
Wk 4	0.4 (-0.0, 0.9)	0.195	-0.0 (-0.3, 0.2)	0.895	0.054
Wk 12	0.0 (-1.1, 1.1)	0.697	0.3 (0.1, 0.6)	0.079	0.419
IL-6
Wk 1	-0.0 (-0.1, 0.1)	0.967	0.0 (-0.1, 0.1)	0.461	0.609
Wk 4	0.2 (-0.2, 0.6)	0.223	0.0 (-0.0, 0.1)	0.643	0.418
Wk 12	0.0 (-0.1, 0.1)	0.260	0.1 (0.0, 0.1)	* 0.043	0.087
IL-8
Wk 1	-1.3 (-3.3, 0.7)	0.662	1.8 (-1.1, 4.6)	0.093	0.087
Wk 4	3.6 (-6.1, 13.3)	0.292	0.2 (-0.1, 0.5)	0.925	0.408
Wk 12	0.6 (-1.6, 2.8)	0.976	0.3 (-1.0, 1.7)	0.978	0.794
IL-9
Wk 1	-0.0 (-0.2, 0.1)	0.478	0.1 (-0.1, 0.3)	0.304	0.190
Wk 4	-0.0 (-0.1, 0.0)	0.546	0.2 (-0.0, 0.4)	0.054	* 0.039
Wk 12	-0.0 (-0.2, 0.2)	0.409	0.0 (-0.1, 0.2)	0.885	0.635
IL-10
Wk 1	-0.0 (-0.3, 0.2)	1.000	0.1 (-0.2, 0.3)	0.523	0.591
Wk 4	0.1 (-0.0, 0.2)	1.000	0.1 (-0.0, 0.2)	0.619	0.693
Wk 12	0.0 (-0.3, 0.4)	1.000	0.3 (0.1, 0.4)	* 0.020	0.087
IL-15
Wk 1	-0.0 (-0.2, 0.2)	0.877	0.0 (-0.1, 0.2)	0.674	0.702
Wk 4	0.0 (-0.1, 0.2)	0.704	0.1 (-0.0, 0.3)	0.372	0.334
Wk 12	-0.0 (-0.3, 0.3)	0.693	0.3 (0.1, 0.5)	* 0.024	0.065
FGF2
Wk 1	-1.3 (-4.6, 1.9)	0.209	1.0 (-2.6, 4.6)	0.539	0.315
Wk 4	0.5 (-1.4, 2.5)	0.891	1.3 (-0.7, 3.3)	0.840	0.568
Wk 12	-0.4 (-4.4, 3.7)	0.561	3.1 (0.3, 5.9)	0.207	0.092
G-CSF
Wk 1	-0.3 (-0.8, 0.2)	0.394	-0.2 (-1.0, 0.7)	0.717	0.785
Wk 4	0.8 (-0.4, 2.1)	0.109	0.4 (-0.9, 1.6)	0.554	0.464
Wk 12	-0.1 (-1.2, 0.9)	0.108	0.5 (-0.2, 1.2)	0.510	0.252
Flt3
Wk 1	-0.1 (-0.5, 0.3)	0.460	0.0 (-0.2, 0.3)	0.761	0.539
Wk 4	0.1 (-0.3, 0.5)	0.789	0.2 (-0.2, 0.5)	0.271	0.814
Wk 12	0.1 (-0.6, 0.8)	0.898	0.1 (-0.3, 0.5)	0.505	0.986
Fractalkine
Wk 1	-1.0 (-6.8, 4.8)	0.668	-0.2 (-6.0, 5.6)	0.949	0.827
Wk 4	1.9 (-3.7, 7.5)	0.468	0.2 (-3.5, 3.9)	0.634	0.568
Wk 12	-2.3 (-6.5, 2.0)	0.584	2.6 (-2.0, 7.2)	0.582	0.097
IFNα2
Wk 1	-0.2 (-1.0, 0.5)	0.237	-0.1 (-1.2, 1.0)	1.000	0.866
Wk 4	0.8 (-0.3, 1.9)	0.245	-0.0 (-0.8, 0.7)	1.000	0.171
Wk 12	-0.0 (-1.0, 0.9)	0.312	0.4 (-0.6, 1.3)	1.000	0.533
GRO
Wk 1	-0.6 (-1.3, 0.1)	0.230	-0.1 (-0.7, 0.5)	0.830	0.236
Wk 4	0.5 (-0.8, 1.9)	0.326	0.5 (-0.7, 1.6)	0.319	0.921
Wk 12	-0.3 (-1.3, 0.7)	0.110	0.5 (-0.1, 1.0)	0.406	0.074
MCP-1
Wk 1	1.1 (-14.8, 16.9)	0.383	2.3 (-13.5, 18.1)	0.770	0.906
Wk 4	-5.5 (-14.7, 3.7)	0.835	2.3 (-12.4, 17.1)	0.655	0.330
Wk 12	-2.3 (-20.9, 16.3)	0.857	-3.5 (-17.1, 10.2)	0.711	0.906
MCP-3
Wk 1	-0.3 (-1.4, 0.7)	0.464	0.1 (-1.0, 1.2)	0.853	0.541
Wk 4	0.3 (-0.4, 1.0)	0.466	0.4 (-0.3, 1.0)	0.783	0.892
Wk 12	-0.1 (-1.5, 1.4)	0.866	1.0 (0.1, 1.9)	0.130	0.122
VEGF
Wk 1	0.3 (-0.4, 1.0)	0.539	-0.4 (-1.3, 0.5)	0.415	0.241
Wk 4	1.2 (0.3, 2.1)	* 0.015	-0.5 (-1.3, 0.7)	0.394	* 0.013
Wk 12	0.3 (-1.3, 1.9)	0.856	0.2 (-0.8, 1.2)	0.744	0.870
Eotaxin
Wk 1	-0.1 (-1.0, 0.9)	1.000	0.0 (-0.5, 0.5)	0.989	0.896
Wk 4	0.2 (-0.3, 0.8)	1.000	0.3 (-0.1, 0.7)	0.452	0.908
Wk 12	0.3 (-0.8, 1.3)	1.000	0.6 (0.3, 0.9)	* 0.030	0.401
RANTES
Wk 1	-0.0 (-0.4, 0.4)	0.999	-0.2 (-0.6, 0.2)	0.335	0.493
Wk 4	4.8 (-5.5, 15.1)	0.176	0.1 (-0.3, 0.5)	0.650	0.285
Wk 12	0.3 (-0.4, 0.9)	0.880	0.2 (-0.2, 0.5)	0.722	0.738
TNF-β
Wk 1	-0.0 (-0.2, 0.1)	0.578	0.1 (-0.1, 0.2)	0.505	0.422
Wk 4	0.0 (-0.1, 0.1)	0.803	0.1 (-0.1, 0.2)	0.570	0.329
Wk 12	-0.0 (-0.2, 0.2)	0.700	0.2 (0.0, 0.3)	0.146	0.082

Values are presented as mean (95% CI).

*: P < 0.05, **: P < 0.01, ***: P < 0.005, ****: P < 0.0001

^a: Generalized estimating equation compared with baseline.

^b: Comparison between corresponding time point of ESWT and placebo (Generalized estimating equation).

Improves Symptoms and Urinary Biomarkers in Refractory Interstitial Cystitis/Bladder Pain Syndrome Patients Randomized to Extracorporeal Shock Wave Therapy Versus Placebo

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Abstract

Figures

Introduction

Materials And Methods

Results

Discussions

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References

Tables

Status:

Journal Publication

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