Interstitial cystitis (IC) is a chronic bladder disease that is characterized by pelvic pain, urinary frequency, and urgency in the absence of other identifiable pathologies such as urinary tract infection or cancer. The precise mechanism and pathophysiology remain poorly understood and potential causes include infection, autoimmune processes, neuronal inflammation, exposure to toxins, psychosomatic factors, detrusor fibrosis, and damage to the glycosaminoglycan (GAG) layer of the bladder urothelium. Many studies have shown that a subset of IC patients have a documented defect of the GAG layer in the bladder mucosa which has led to a variety of intravesical instillation medications such as hyaluronic acid (HA), chondroitin sulfate and pentosan polysulfate being utilized to restore the GAG layer and treat IC. Bladder instillation of HA has become a widely acceptable treatment option for IC patients. Previous studies have shown varying degrees of success in treatment outcomes. Such diverse treatment success could be related to individual variations in the severity of disease, differences in the protocol of instillation, and methods of assessing outcome measures in each study. Intravesical HA therapy is indicated for cystoscopic IC refractory to conventional treatment in Taiwan and is reimbursed by the national health insurance after prior review. The aim of this study was to conduct a systematic review of studies using intravesical HA instillations for the treatment of refractory IC in Taiwan and to determine the efficacy and safety of this treatment modality in this homogeneous patient population.

This study was designed and conducted in accordance with the PRISMA 2020 statement. EMBASE, PubMed, and The Cochrane Library were searched from inception until December 2023 to identify relevant studies. The search strategy included a combination of the following keywords: interstitial cystitis/bladder pain syndrome (IC/BPS), interstitial cystitis (IC), bladder pain syndrome (BPS), painful bladder syndrome, intravesical treatment, hyaluronic acid (HA), and Taiwan. Articles were considered for inclusion if they were studies evaluating the effectiveness of intravesical hyaluronic acid instillations on interstitial cystitis/bladder pain syndrome in Taiwan. There was no restriction on the type of study or clinical outcomes reported in the study. Articles were excluded if they were studies of non-human subjects, or in vitro studies; studies with data not reliably extracted, duplicate, or overlapping data; abstract-only papers as preceding papers, conference, editorial, and author response theses and books; articles without full text available; or case reports, case series, and systematic review studies. The main outcomes of interest included the response rate, pain-VAS scores, and changes in urodynamic parameters.

Eight articles were identified that met the inclusion criteria and the PRISMA flow diagram was presented in Figure 1. Study characteristics were presented in Table 1. The eight studies recruited a total of 427 participants with IC and included one randomized control trial, two multicenter prospective cohort studies, three single-site prospective cohort studies, one retrospective single-site cohort study, and one secondary analysis of a multicenter prospective cohort study. All IC patients were diagnosed via the guidelines published either by the European Society for the Study of Interstitial Cystitis (ESSIC) or the East Asian guidelines. The most commonly used HA instillation regimen was that of four weekly bladder instillations, each with 40mg/50mL of a commercial HA solution, followed by five monthly bladder instillations for a total treatment time of six months.
All studies which included data on pain, ICSI, and ICPI scores, found a statistically significant decrease in all scores across the board post-HA treatment. Studies that included analysis of global response assessments (GRA) on bladder pain, bladder storage, and overall bladder conditions showed moderately or markedly improved symptoms in the majority of patients after HA treatment. The reported response rate was around 60-70%. Five studies included three-day voiding diary analysis and found statistically significant decreases in frequency and nocturia accompanied with statistically significant increases in bladder capacity. Interestingly, studies found no differences in urgency after HA treatment. Four studies included urodynamic studies with results varying between studies with the majority of studies finding no statistically significant differences post-HA treatment in parameters such as voided volume, postvoid residual, residual urine, and maximum flow rate. Of the three studies that included data on sexual function, two studies found significant increases in PISQ scores at 1-month and 6-month follow-up when compared to baseline with significant improvements in the three parameters of dyspareunia, negative reactions, and intensity of orgasms.

While types of clinical outcomes measured varied widely among the eight studies included in this review, urinary frequency, bladder capacity, the O’Leary-Sant index Symptom and Problem Index (ICSI/ICPI), and pain-VAS score were the most commonly analyzed. Studies found statistically significant decreases in frequency and nocturia accompanied by statistically significant increases in bladder capacity. On average, the bladder capacity increased by 43.3 mL at six-months follow-up after hyaluronic acid instillation. These findings correlated well with those of previous reviews which also found improvements in bladder capacity and voiding frequency post-HA treatment. Clinical parameters including pain, ICSI, and ICPI scores all had statistically significant changes post-HA instillation. There was a statistically significant decrease in ICPI and ICSI scores along with an average decrease of 2.11 points in the pain-VAS between baseline and six months post-treatment. These decreases in pain-VAS, ICSI, ICPI, and GRA were all able to be sustained for at least six months with one study showing decreases sustained for up to nine months after the last HA instillation. However, one study noted that while there was a clear decrease in average pelvic pain scores in patients pre- and post-treatment, a high percentage of patients still reported mild or greater pelvic pain after treatment. These findings were consistent with previous studies which found marked improvements in pain scores post-treatment but that a certain subset of patients would still have lingering symptoms so continued instillation as a maintenance therapy is warranted to control the pain symptoms. This further proves that IC is a chronic disease and most patients need maintenance therapy to achieve a satisfactory quality of life. Previous studies have shown that the tolerability of the intravesical hyaluronic acid instillation therapy is high and the rate of adverse effects is low. Of the 427 participants included in this review, there were no drop-outs due to intolerability of the instillation regimen and there were no reported serious adverse effects or complications related to the treatment. These experiences indicated that intravesical HA therapy is a safe and tolerable treatment regimen for IC patients.

Intravesical HA therapy had been used for patients with cystoscopic IC refractory to conventional treatment in Taiwan for many years. After the review, we found the treatment is safe and effective for most (60-70%) of our patients and the results are consistent among the enrolled studies. Intravesical HA therapy can significantly improve bladder pain, lower urinary tract symptoms, bladder capacity, and sexual function after a full course (usually 6 months) of treatment. However, there is a notable percentage (30-40%) of non-responders who have lingering symptoms after the treatment. In the future, further studies are needed to determine whether a prolonged maintenance therapy and/or additional treatment such as pelvic floor physiotherapy, oral medications, Botox bladder injection and sacral neuromodulation, etc., may further benefit these patients.

Abrams, P., et al., The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology, 2003. 61(1): p. 37-49.
Hung, M.J., et al., Hyaluronic acid improves pain symptoms more than bladder storage symptoms in women with interstitial cystitis. Taiwan J Obstet Gynecol, 2019. 58(3): p. 417-422.
Tsai, C.P., et al., Factors associated with treatment outcomes after intravesical hyaluronic acid therapy in women with refractory interstitial cystitis: A prospective, multicenter study. J Chin Med Assoc, 2021. 84(4): p. 418-422.