Role of urinary cations in the etiology of interstitial cystitis: A multisite study.

OBJECTIVE: To determine whether patients with interstitial cystitis have elevated levels of toxic urinary cations, to identify and quantify these cationic metabolites, and to assess their cytotoxicity. METHODS: Isolation of cationic fraction was achieved by solid phase extraction using an Oasis MCX cartridge on urine specimens from interstitial cystitis patients and controls. C18 reverse phase high-performance liquid chromatography was used to profile cationic metabolites, and they were quantified by the area under the peaks and normalized to creatinine. Major cationic fraction peaks were identified by reverse phase high-performance liquid chromatography and liquid chromatography-mass spectrometry. HTB-4 urothelial cells were used to determine the cytotoxicity of cationic fraction and of individual metabolites. RESULTS: The reverse phase high-performance liquid chromatography analysis was carried out on cationic fraction metabolites isolated from urine samples of 70 interstitial cystitis patients and 34 controls. The mean for controls versus patients was 3.84 (standard error of the mean 0.20) versus 6.71 (0.37) mAU*min/µg creatinine, respectively (P = 0.0001). The cationic fraction cytotoxicity normalized to creatinine for controls versus patients in mean percentage was -7.79% (standard error of the mean 3.32%) versus 20.03% (standard error of the mean 2.75%; P < 0.0005). The major toxic cations were 1-methyladenosine, 1-methylguanine, N2 ,N2 -dimethylguanosine and L-tryptophan. CONCLUSIONS: These data confirm significant elevation of toxic cations in the urine of interstitial cystitis patients. These toxic cations likely represent a primary cause of interstitial cystitis, as they can injure the bladder mucus and initiate an epithelial leak.

A randomized, double-blind, placebo controlled trial of adalimumab for interstitial cystitis/bladder pain syndrome.

PURPOSE: The efficacy of adalimumab for the treatment of interstitial cystitis/bladder pain syndrome was investigated in a phase III, randomized, double-blind, placebo controlled, proof of concept study. MATERIALS AND METHODS: Patients with interstitial cystitis/bladder pain syndrome were randomized to receive a loading dose of 80 mg subcutaneous adalimumab followed by 40 mg every 2 weeks or subcutaneous placebo for 12 weeks, and outcome measures were assessed. The incidence of adverse events was also assessed. RESULTS: Of a total of 43 patients 21 received adalimumab and 22 received placebo. Of the patients who received adalimumab, there was a statistically significant improvement demonstrated in the O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes (p = 0.0002), Interstitial Cystitis Symptom Index (p = 0.0011), Interstitial Cystitis Problem Index (p = 0.0002), and Pelvic Pain, Urgency, Frequency Symptom Scale (p = 0.0017) at 12 weeks compared to baseline. At 12 weeks 11 of 21 (53%) patients in the adalimumab group had a 50% or greater improvement in global response assessment (p ≤ 0.0001). There was not a statistically significant improvement in any outcome measure in patients receiving adalimumab compared to placebo. There were no significant adverse events. CONCLUSIONS: Adalimumab treatment resulted in a statistically significant improvement in outcome measures compared to baseline in patients with moderate to severe interstitial cystitis/bladder pain syndrome. Adalimumab failed to demonstrate positive proof of concept compared to placebo due to a significant placebo effect.

A Randomized, Double-blind, Placebo-controlled Trial of Certolizumab Pegol in Women with Refractory Interstitial Cystitis/Bladder Pain Syndrome.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic, disabling bladder disease, with an uncertain pathophysiology and no universally effective treatment. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol compared with placebo in women with refractory IC/BPS. DESIGN, SETTING, AND PARTICIPANTS: Eligible women, aged 18-65 yr with moderate to severe IC/BPS, were enrolled in this randomized, double-blind, placebo-controlled pilot study. INTERVENTION: Study patients were randomized at a 2:1 ratio to receive either certolizumab pegol or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome measure was a patient-reported global response assessment (GRA). Secondary endpoints included Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), and a numeric rating scale for pain and urgency. RESULTS AND LIMITATIONS: The primary endpoint of GRA improvement at week 2 was not met. However, by week 18, there was significant improvement in GRA for certolizumab pegol compared with placebo in pain (odds ratio [OR]=17.3, p=0.002), urgency (OR=9.92, p=0.02), and overall symptoms (OR=15.0, p=0.006). At week 18, there was a statistically significant improvement for certolizumab pegol compared with placebo in change from baseline for ICSI of -3.6 (95% confidence interval [CI]: -6.9 to -0.29, p=0.03), ICPI of -3.0 (95% CI: -6.1 to 0.12, p=0.042), pain scale of -2.0 (95% CI: -3.9 to -0.15, p=0.02), and urgency scale of -1.7 (95% CI: -3.5 to 0.06, p=0.03). There was a significant difference in greater than 30% reduction in pain from baseline comparing certolizumab pegol with placebo at week 18 (OR=13.0, p=0.02). Limitations include a larger, longer, multicenter trial is warranted with phenotypic categorization of patients. CONCLUSIONS: Women with moderate to severe refractory IC/BPS were more likely to experience significant improvement in symptoms with certolizumab pegol compared with placebo therapy. Further investigation of certolizumab pegol for the treatment of IC/BPS is warranted with a larger, longer, multicenter, randomized, placebo-controlled trial. PATIENT SUMMARY: Women with moderate to severe interstitial cystitis/bladder pain syndrome were helped with a medication used to treat autoimmune diseases.

Examination of the significant placebo effect in the treatment of interstitial cystitis/bladder pain syndrome.

OBJECTIVE: To examine the significant "placebo effect" in a randomized, double-blind, placebo-controlled interstitial cystitis/bladder pain syndrome trial. Randomized clinical trials are the reference standard for therapeutic impact assessment. However, proving efficacy of treatments for interstitial cystitis/bladder pain syndrome with rigorous placebo-controlled trials is difficult due to a significant effect of the placebo intervention. METHODS: Interstitial cystitis/bladder pain syndrome patients were randomized to receive subcutaneous adalimumab or subcutaneous placebo every 2 weeks for 12 weeks and outcome measures were assessed. RESULTS: Of the 43 patients, 21 received adalimumab and 22 received placebo. Of the patients who received placebo, there was a statistically significant improvement demonstrated in the O'Leary-Sant Interstitial Cystitis Symptom and Problem Indexes of -8.1 (95% confidence interval [CI], 3.0-13.2), Interstitial Cystitis Symptom Index of -3.7 (95% CI, 0.9-6.5), Interstitial Cystitis Problem Index of -4.4 (95% CI, 2.0-6.8), and Pelvic Pain, Urgency, Frequency scale of -6.9 (95% CI, 2.8-11.0) at week 12 compared with baseline. Most of the significantly improved placebo patients felt their improvement was because they were more conscientious about following physician advice and feeling less stress while in the study. CONCLUSION: Patients with moderate to severe interstitial cystitis/bladder pain syndrome had significant improvement after receiving only advice and support. This intervention is risk free and inexpensive. Physicians should review standard advice with all interstitial cystitis/bladder pain syndrome patients before starting medical therapy.

Treating interstitial cystitis/bladder pain syndrome as a chronic disease.

The management of interstitial cystitis/bladder pain syndrome (IC/BPS) is both frustrating and difficult. The etiology is uncertain and there is no definitive treatment. Consequently, both patients and doctors tend to be unhappy and unsatisfied with the quality of care. The American Urological Association (AUA) provides a guideline for the diagnosis and treatment of IC/BPS. Recommended first-line treatments include patient education, self-care practices, behavior modifications, and stress management. Management of IC/BPS may be also improved if both patients and doctors treat this condition as a chronic disease. This article reviews the AUA first-line treatments for IC/BPS and considers the benefits of treating this condition as a chronic disease.