Background/Aims: To assess the efficacy of intravesical hyaluronic acid (HA) and HA/chondroitin sulfate (CS) instillation in patients with interstitial cystitis/painful bladder syndrome by systematic review and meta-analysis. Methods: A systematic literature search was performed using the keywords: ‘interstitial cystitis' or ‘painful bladder syndrome' or ‘bladder pain syndrome' and ‘hyaluronic acid', up to March 31, 2016. The primary outcome was visual analogue scale related pain symptom (VAS). Secondary outcomes were the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and Problem Index (ICPI), frequency, nocturia, bladder volume, and voided urine volume. Results: Ten articles involving 390 patients were retrieved and assessed in analysis. A significant improvement in mean VAS on fixed-effect and random-effect models (mean difference [MD] -3.654, 95% confidence interval [CI] -3.814 to -3.495, and MD -3.206, 95% CI -4.156 to -2.257, respectively) was found. Significant improvements were found in the ICSI (MD -3.223, 95% CI -4.132 to -2.315) and ICPI (MD -2.941, 95% CI -3.767 to -2.116). Similarly, the other outcomes were significantly improved. Conclusion: Intravesical HA and HA/CS instillation improved pain symptom, quality of life, and other outcomes and could be included as therapeutic modality of interstitial cystitis/painful bladder syndrome.
Generally, inflammatory conditions of the bladder produce suprapubic or pelvic pain. Thus, pain in conditions such as cystitis is usually most severe when the bladder is full and is relieved at least partially by voiding. Therefore, many patients with bladder inflammation reveal lower urinary tract symptoms such as frequency, nocturia, urgency, and residual urine sense. Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory condition of the bladder wall characterized by bladder and pelvic pain, urinary urgency, frequency, and nocturia in the absence of other identified causes for the symptoms and has a negative impact on quality of life [1,2,3]. Although various prevalence rates were reported according to the definitions used, the prevalence rates in women is about 300/100,000 and the prevalence rate in men is 10% to 20% that of women . The etiology of IC/PBS is still not well understood and different hypotheses have been suggested, including infection, autoimmune processes, dysfunctional urothelium, mast cell activation, neuronal inflammation, exposure to toxins or dietary elements, and psychosomatic factors [4,5]. It has been hypothesized that IC/PBS could be pathophysiologically related to a defect of the glycosaminoglycan (GAG) layer of the bladder mucosa . The relevant components of the GAG layer include hyaluronic acid (HA), heparin sulfate, chondroitin sulfate (CS), dermatan sulfate, and keratin sulfate [7,8]. According to this theory, some drugs that aim at improving the integrity of the GAG layer and functioning of the urothelial barrier have been evaluated for IC/PBS, such as pentosan polysulfate, heparin sulfate, HA, CS, or combinations of these drugs [9,10,11,12]. Specifically, HA represents an important portion of the GAG layer, and several studies have reported that HA instillation provided positive effects for patients with IC/PBS [11,13]. Furthermore, intravesical HA instillation is recommended as a therapeutic option in recent guidelines [14,15]. To assess the efficacy of intravesical HA instillation in patients with IC/PBS, we performed a systematic review and meta-analysis including the recent evidences.
Materials and Methods
Published study search and selection criteria
Relevant articles were obtained by searching the PubMed, MEDLINE, and ScienceDirect databases up to March 31, 2016. Searches were performed using the following key words: ‘interstitial cystitis' or ‘painful bladder syndrome' or bladder pain syndrome' and ‘hyaluronic acid'. The title and abstract of all retrieved articles were screened for exclusion. In addition, review articles were screened to find additional eligible studies. The search results were then limited according to the following inclusion and exclusion criteria: (1) intravesical HA instillations were performed in human subjects with IC/PBS, (2) articles involved follow-up results at 6 months, (3) articles were reported in English, and (4) non-full-text articles were excluded.
Two authors extracted the data from all eligible studies. The following data were extracted from each of the eligible studies [16,17,18,19,20,21,22,23,24,25]: the first author's name, year of publication, number of patients, patients' ages, products used, instillation regimens, visual analogue scale related pain symptom (VAS), total scores of the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and Problem Index (ICPI), storage symptoms such as frequency and nocturia, bladder volume, and voided urine volume. Any disagreements were resolved by consensus. The primary outcome was the change in VAS from baseline to the 6-month follow-up period. The secondary outcomes were the changes in ICSI and ICPI, storage symptoms, bladder volume, and voided urine volume.
To perform the meta-analysis, all data were analyzed with the Comprehensive Meta-Analysis software package (Biostat, Engelwood, NJ, USA). All outcome data were analyzed and presented with 95% confidence intervals (CI) in the form of mean difference (MD) by fixed-effects and random-effects models. A sensitivity analysis was conducted to assess the heterogeneity of eligible studies and impact of each study on the combined effect. In addition, the heterogeneity between studies was checked by using the Q and I2 statistics and demonstrated p-value. In addition, to compare the effects between HA alone and HA-based agent, we performed a subgroup analysis and meta-regression test in HA and HA/CS subgroups. For assessment of publication bias, the Begg's funnel plot and Egger's test were performed. If a significant publication bias was found, the fail-safe N and trim-fill tests were additionally conducted to confirm the degree of publication bias. The results were two-sided and considered statistically significant when p < 0.05.
Selection and characteristics of studies
In total, we identified 201 reports by searching the databases. Of these reports, 177 reports were excluded based on the following criteria: insufficient or no information for efficacy results during the follow-up period (68), non-original articles (52), studies using animal or cell lines (16), articles not in English (13), studies of other diseases than IC/PBS (13), studies using other drugs (1), and duplication (14) in the primary selection process. In addition, 14 articles were excluded at further assessment for eligibility because of insufficient or no information (7), studies of other diseases than IC/PBS (6) and duplication (1). Most studies related to IC/PBS used the pain-related symptom score as the primary outcome. The final systematic review and meta-analysis included 10 eligible articles and 8 subsets with HA and 4 subsets with HA/CS. However, analyzed studies numbered 12 in the current meta-analysis because Gulpinar et al.  reported the results of Hyacyst® (120 mg HA in 50 ml) and Ialuril® (1.6% HA and 2.0% CS), and Lai et al.  reported the separate results of HA instillation for IC/PBS with 2 different regimens: 4 weekly intravesical instillations of 40 mg HA followed by 5 monthly HA instillations (HA-9 group), and 12 intravesical instillations of 40 mg HA every 2 weeks (HA-12 group). Therefore, we counted these as 4 studies in the data extraction process (Table 1) after searching the articles (Fig. 1). The total number of patients was 390, and most patients were female. The other characteristics of the studies are summarized in Table 1.
Primary outcome, visual analogue scale related pain symptoms (VAS)
First, we investigated the effect of HA or HA/CS on the VAS. We found a significant improvement in mean VAS on both fixed-effect and random-effect models (MD -3.654, 95% CI -3.814 to -3.495 and MD -3.206, 95% CI -4.156 to -2.257, respectively) (Table 2). This beneficial effect was consistent among 9 studies (Fig. 2A). Eligible studies showed significant heterogeneity (I2 = 97%, p < 0.001). A sensitivity analysis was performed to assess the impact of each study on the combined effect and no single study had a significant effect on the pooled VAS. The MD range of the VAS was -2.921 to -3.431 in the sensitivity analysis. In the subgroup analysis, mean differences of VAS were -3.298 (95% CI -4.433 to -2.163) and -2.938 (95% CI -3.803 to -2.073) in pure HA and a combination of HA and CS subgroups, respectively. There was no significant difference between two agents (P = 0.722) in the meta-regression test (Table 2). In the assessment of publication bias, Begg's funnel plot and Egger's test were preferentially performed and no definitive publication biases were found. (Table 2 and Fig. 2B).
Significant improvements were found in ICSI (MD -3.223, 95% CI -4.132 to -2.315) and ICPI (MD -2.941, 95% CI -3.767 to -2.116) (Table 2). Additionally, significant improvements were found in bladder volume and voided urine volume (bladder volume: MD 59.89, 95% CI 11.33 to 108.46, voided urine volume: MD 30.83, 95% CI 15.09 to 46.57). In the sensitivity analysis, all studies were not affected by the pooled mean values. In addition, both the pure HA and HA/CS subgroups showed improvement in the pooled mean values of all secondary outcomes. There was no significant publication bias in Begg's funnel plot and Egger's test (Table 2).
IC/PBS is a challenge to the urologist because of its unknown etiology and the unpredictable effects and durability of conventional treatments including oral therapies, intravesical therapies, and surgical interventions. For these reasons, various therapeutic modalities have been attempted.
Among these therapeutic modalities, intravesical treatment with various agents has been reported, and response rates after initial instillation therapy were 45% for CS, 56% for heparin, and 44% for pentosane polysulfate [10,26,27]. Other authors reported respectably higher response rates with intravesical HA therapy, and the beneficial effect was maintained for more than 3 years . We performed a meta-analysis on studies including follow-up results at 6 months, and we were able to observe a significant improvement with intravesical HA instillation.
Presently, the optimal intravesical instillation regimen with HA has not been defined. Lai et al. compared the clinical effectiveness of two different intravesical HA instillation regimen (HA-9: 4 weekly intravesical instillations of 40 mg HA followed by 5 monthly HA instillations HA-12: 12 intravesical instillations of 40 mg HA every 2 weeks) . However, most studies adopted a treatment strategy consisting of weekly treatment for several weeks followed by maintenance treatment (Table 1). Engelhardt et al. reported that after HA therapy 50% of patients showed complete bladder symptom remission at 5 years of follow-up without any additional therapy and 41.7% of patients with symptom recurrence showed improvement with HA maintenance therapy . In our analysis, a significantly positive effect at 6 months of follow-up was demonstrated. Thus, we think that maintenance treatment should be determined by patients' responses after initial weekly treatment for several weeks and continued over 6 months if possible, even though more long-term studies are required to assess the HA effect durability in patients with IC/PBS.
Several studies evaluated CS, a component of the GAG layer, as intravesical instillation therapy for IC/PBS patients. Steinhoff et al. found a 45% response rate after initial 3 months with instillation of 40 ml CS 0.2%, and Nickel et al. reported that instillation of CS 2% produced a 60% response rate at 6 months [27,29]. Furthermore, several studies also reported a significant effect with the combination of HA and CS, Porru et al. assumed that HA/CS may give better longer-lasting therapeutic effects than the individual compounds [17,23,30]. In the present study, although mean difference of VAS in the pure HA subgroup was higher than that in the subgroup with combination of HA and CS, there was no significant difference between subgroups (P = 0.722). In a clinical comparison of intravesical HA and HA/CS therapy for IC/PBS, Gulpinar et al. reported that improvements in pain, frequency, nocturia, ICSI, and ICPI were statistically significant at 6 months for each treatment group, but there was no difference between both groups . HA does not appear to be integrated into cell membrane proteoglycans but binds to a number of receptors expressed by urothelial cells. On the other hand, CS needs to be integrated into cell membrane proteoglycans by active synthesis in an energy-consuming intracellular process to exert its barrier properties [24,31]. The higher water binding capacity of HA compared to CS may result in a superior barrier effect. Although the effects of additional CS is not clear, larger long-term studies may be necessary to assess any possible difference between HA and HA/CS.
In 2010, Shao et al. reported the results of intravesical instillation of 40 mg HA and heparin after bladder hydrodistention . There was no improvement in hydrodistention alone at 3 months, but the rate of improvement in the HA group was significantly higher than in the heparin group at 6 and 9 months (77.8% vs 33.3%, p < 0.05; 50% vs 20%, p < 0.05, respectively). Thus, they concluded that HA may prolong the effect of bladder hydrodistention in patients with severe IC.
Regarding tolerability of intravesical HA instillation, mild adverse events were reported such as urinary tract infection (0-17.4%), temporary worsening of storage symptoms (0-11.3%), and events related to catheterization [13,17,18,22,23]. In addition, serious adverse events or adverse reactions by agents were not shown. Riedl et al. reported that there were no adverse reactions over the whole treatment period with a total of 1,521 instillations . Thus, we think that intravesical HA instillation is well tolerated and can be performed with careful catheterization and prophylactic antibiotics.
In conclusion, our results showed the significant effects of intravesical HA, alone or in combination with CS, instillation on pain symptom, quality of life and other outcomes, although long-term and placebo-controlled studies were few. Recent guidelines related to IC/PBS recommend multiple, simultaneous treatments after thorough evaluation and sufficient consultation. Thus, we think that intravesical HA, alone or in combination with CS, instillation could be considered as a component of therapeutic strategy for optimal results from IC/PBS.
The authors declare that they have no conflict of interest.