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Int Urogynecol JDOI 10.1007/s00192-010-1294-y Long-term results of intravesical hyaluronan therapyin bladder pain syndrome/interstitial cystitis Paul F. Engelhardt & Nike Morakis & Lukas K. Daha &Britta Esterbauer & Claus R. Riedl Received: 2 August 2010 / Accepted: 20 September 2010 # The International Urogynecological Association 2010 Introduction and hypothesis While the short-term efficacyof intravesical hyaluronan for bladder pain syndrome/ Glycosaminoglycan (GAG) substitution therapy is one of the interstitial cystitis (BPS/IC) has been demonstrated, no data most popular regimens for treatment of BPS/IC. Response rates exist on the long-term outcome of this therapy.
between 30% and 80% have been described with intravesical Methods Seventy BPS/IC patients treated with intravesical administration of various substances like hyaluronan, pentosan hyaluronan therapy from 2001 to 2003 were asked to rate their polysulfate (PPS), heparin; chondroitin sulfate, and DMSO.
present status of bladder symptoms on a visual analog scale.
Most of these studies were uncontrolled and short-term Results Forty-eight of 70 patients responded after a mean observational. Despite acceptable response rates in these follow-up of 4.9 years. The average initial VAS score of 8.15 reports, no significant advantage over placebo was found when had been reduced to 2.71 after therapy and further to 2.14 5 years later. Fifty percent of patients (24/48) reported One of the largest published series on intravesical hyalur- complete bladder symptom remission at 5 years follow-up onan therapy in BPS/IC from our institution showed >80% without any additional therapy; 41.7% (20/48) with symptom symptom response rate 6 months after treatment in a therapy- recurrence was improved with hyaluronan maintenance naïve group of patients selected by a positive modified therapy. No improvement was reported by four patients.
potassium test []. Since long-term follow-up data for patients Conclusions Besides a high rate of acute symptom remis- after instillation therapy are only addressed in a single study sion, intravesical hyaluronan also shows long-term efficacy from Kallestrup for a small patient cohort ], we assessed in a considerable number of BPS/IC patients.
the present bladder symptom status of our patients 5 yearsafter instillation therapy.
Keywords Bladder pain syndrome . GAG substitution .
Hyaluronan . Hyaluronic acid . Instillation therapy .
Interstitial cystitis Seventy female patients with the diagnosis of BPS/IC P. F. Engelhardt (*) : N. Morakis : C. R. Riedl Department of Urology, Landesklinikum Thermenregion Baden, bladder pain syndrome (BPS) is made on the basis of the symptom of pain related to the urinary bladder, accompa- nied by at least one other urinary symptom such as day-time and night-time frequency, as well as exclusion of L. K. DahaDepartment of Urology, Krankenhaus Hietzing, confusable diseases as the cause of the symptoms”) who had been treated with intravesical hyaluronan 40 mg in50 cm3 phosphate-buffered saline (Cystistat®, Bioniche, Urologic Clinic, Paracelsus University of Medicine, with a questionnaire by mail. Patients were selected for hyaluronan therapy by a positive modified potassium test, i.
symptoms recurred during the first year after initial e., patients had to show a >30% reduction of maximal improvement in 20/48 patients (41.7%). These recurrences bladder capacity in a consecutive instillation of saline were treated with another course of weekly hyaluronan (NaCl 0.9%) and KCl 0.2 M as described by Daha et al.
instillations followed by monthly maintenance therapy in These patients received weekly hyaluronan instilla- 12 patients, supported by a daily dose of oral pentosanpo- tions until symptoms resolved as to patients judgement or if lysulfate in another eight patients. The VAS at present instillation therapy turned out to be ineffective after a follow-up for this group with maintenance treatment was maximum of 10 instillations. Instillation therapy was only 2.4. The four nonresponders were also treated with a performed in patients who were able to retain the combination of intravesical hyaluronan and oral PPS to maximize GAG substitution therapy, and later with The questionnaire was identical to questionnaires before alternative therapies like amitryptilin, however, without and after instillation therapy as published before and asked VAS scores before therapy and throughout follow-up are shown in Tables and as well as Fig. . The 1. The present status of global bladder symptoms (“Please average initial VAS score for all patients was 8.15 (SD ± rate the presently perceived intensity of your bladder 1.67), decreased to 2.71 (SD ± 1.96) immediately after symptoms”) by a visual analog scale (VAS, 0 to 10, hyaluronan therapy, stayed stable at 6 months post where 0 is no symptoms and 10 is intolerable bladder instillation therapy with an average 2.7 (SD ± 2.1), and showed a further reduction to 2.14 (SD ± 2.31) 5 years 2. Additional therapies within the last 5 years later. VAS score reduction after therapy was statistically 3. And a global judgement of instillation therapy (“Would you undergo instillation therapy again?” and “Would A VAS score reduction of >2 was observed in 85.4% of you recommend instillation therapy to other patients?”) patients (41/48), whereas 6.25% (3/48) showed a reduction Improvement was defined as a VAS score reduction of <2%, and 8.3% (4/48) reported no improvement. While initial VAS scores were similar for three treatment groups Statistical analysis was performed by Friedman ANOVA (group 1: single course of intravesical hyaluronan with and Kendall Coefficient of Concordance Test (p<0.05) and permanent remission, group 2: repeat course and mainte- nance of hyaluronan therapy, group 3: maintenance withintravesical hyaluronan and oral PPS), group 1 had thelowest VAS score after 5 years of follow-up (1.4) vs. 2.4 in group 2 and 4.1 in group 3 that included the fournonresponders.
The response rate to the questionnaire was 68.5% (48 of 70 No statistical correlation was found between patient age patients). Patients’ demographics are shown in Table or duration of BPS/IC symptoms and the grade of symptom Average patients’ age was 48.3 years (17–81), and the average time period after the last instillation was 4.9 years(4–6.8). The average duration of bladder symptoms in thispatients group had been 6.1 years (0.5–12 years) before initiation of treatment. The average number of instillationswas 11.8 (8–25).
The efficacy of hyaluronan is based on several mechanisms Table shows the long-term outcome of hyaluronan that aim on the urothelial function disorder present in BPS/IC: instillation therapy: 50% of patients (24/48) were free of on one side, hyaluronan reinforces the urine-tissue barrier by bladder symptoms after hyaluronan instillation therapy for integration in the GAG layer on the luminal surface and the the whole observation period; their VAS was 1.4 at present base of urothelial cells; on the other side, unique antiin- follow-up. While only 8.3% (4/48) of patients did not flammatory mechanisms have been identified, like inhibition experience any benefit from hyaluronan therapy, bladder of leukocyte migration, adherence of immune complexes, and Mean disease duration before hyaluronan therapy Total numbers of hyaluronan instillations mean Table 2 Long-term follow-up after initial hyaluronan instillation therapy Stable symptom improvement after primary therapy without any further therapy during follow up Stable symptom improvement with intermittent hyaluronan instillation therapy during follow up Stable symptom improvement with intermittent hyaluronan instillation therapy and oral PPS during follow up binding to specific receptors (I-CAM 1, CD 44) involved in treated with intravesical hyaluronan for 3 months (four weekly and two monthly instillations) and were followed The present report is the first that assesses treatment for 3 years. After the initial 3 months of treatment, 65% of results 5 years after hyaluronan instillation therapy. Even patients reported symptom improvement (nocturia was with the setback of an uncontrolled study and a nonre- reduced 40%, pain 30%) and continued monthly hyalur- sponse rate to the questionnaire of 31.5% which reduces the onan instillations up to 3 years. About 50% of these response rate in an intention-to-treat analysis to 34%, there patients stopped therapy within this 3 years period because are several important conclusions that can be drawn from of complete symptom remission, while the other 50% still kept monthly maintenance therapy and were judged aspartial responders. These data are confirmed by the present 1. Intravesical hyaluronan therapy may lead to persistent symptom remission in a selected group of BPS/IC Similar results as in the present study have not been patients. In conventional terms, these patients, 50% in reported for other GAG substituents. Response rates after the present survey, may be regarded as cured from their initial instillation therapy were 45% for chondroitin sulfate, disease. However, late recurrences surpassing the 56% for heparin, and 44% for PPS Long-term results observation period cannot be excluded.
2. Part of the patients with symptom remission after The high response rate in the present study may be a intravesical hyaluronan therapy relapses early within consequence of patient selection and standardization of the first year; however, treatment response was main- tained by continuation of instillation therapy through-out the whole observation period. In some patients, oral 1. The modified potassium test is believed to indicate a PPS was added to the GAG substitution regimen, if disorder at the urine-tissue barrier. Only patients with a either they were not able to regularly come to positive test were included in the present study. This set instillations for an extended period of time or if of patient responds better to GAG substitution therapy, hyaluronan therapy alone did not improve symptoms whereas potassium negative patients show a very low response rate of about 20% –Only recently, it 3. Hyaluronan long-term therapy has no adverse effects was shown that successful hyaluronan instillation and can be administered over years without disadvan- therapy with symptom remission reverses positive The only comparable long-term results were reported by 2. Patients were treatment-naive for BPS/IC, i.e. hyaluronan Kallestrup in this series, 20 BPS/IC patients had been therapy was their first disease-specific therapy. Patients VAS reduction 5 years after initial hyaluronan therapy VAS 1–2 (mild symptoms, no subjective need for therapy) VAS >2 (moderate symptoms, request for therapy) Table 4 VAS scores in responders, maintenance therapy and non-responder groups Group 1 (CR after HA) Group 2 (HA maintenance) Group 3 (PPS+HA maintenance) responders non-responders CR complete remission, Ha hyualuronian, PPS pentosan polysulfate with a number of unsuccessful preceding treatments which counteract the beneficial effect of intravesical represent a negative selection of possibly advanced or neuropathic disease, which usually does not respond to 5. The 8.3% of patients that did not respond to hyaluronan instillation therapy stayed unimproved after 5 years, i.e.
3. The average number of instillations was almost 12 in also other therapies that were initiated during this the present series and, thus, appreciably higher than in period did not influence symptomatology. This subset the reports of other investigators that normally used a of BPS/IC patients stays the “hard core” that needs to schedule of four weekly followed by two to four be subject of future investigations.
4. To be eligible for the protocol, patients had to be able In summary, besides a high rate of acute symptom to retain the hyaluronan instillation for at least 2 h.
remission, intravesical hyaluronan also showed long-term Shorter bladder contact times show less efficacy. Thus, efficacy in a considerable number of BPS/IC patients in the patients with low bladder capacities (and possibly more present study, which suggests that some patients may be advanced disease) were not included. Anti-infective cured by this therapy. Patients with symptom recurrence prophylaxis with nitrofurantoin 50 mg on instillation after instillation therapy have a high chance for symptom days prevented bladder infections from catheterism, remission with hyaluronan maintenance therapy.
Fig. 1 Box plot figure of VASsymptom score during follow-up Claus R. Riedl is the principal investigator for 9. Riedl CR, Engelhardt PF, Daha KL, Morakis N, Pflüger H (2008) controlled study on Hyaluronan in BPS/IC (CISTIC).
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