Long-term results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial cystitis

Abstract

While the short-term efficacy of intravesical hyaluronan for bladder pain syndrome/interstitial cystitis (BPS/IC) has been demonstrated, no data exist on the long-term outcome of this therapy.
Seventy BPS/IC patients treated with intravesical hyaluronan therapy from 2001 to 2003 were asked to rate their present status of bladder symptoms on a visual analog scale.
Forty-eight of 70 patients responded after a mean follow-up of 4.9 years. The average initial VAS score of 8.15 had been reduced to 2.71 after therapy and further to 2.14 5 years later. Fifty percent of patients (24/48) reported complete bladder symptom remission at 5 years follow-up without any additional therapy; 41.7% (20/48) with symptom recurrence was improved with hyaluronan maintenance therapy. No improvement was reported by four patients.
Besides a high rate of acute symptom remission, intravesical hyaluronan also shows long-term efficacy in a considerable number of BPS/IC patients.

Full text

ORIGINAL ARTICLE
Long-term results of intravesical hyaluronan therapy
in 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
Abstract
Introduction and hypothesis While the short-term efficacy
of intravesical hyaluronan for bladder pain syndrome/
interstitial cystitis (BPS/IC) has been demonstrated, no data
exist on the long-term outcome of this therapy.
Methods Seventy BPS/IC patients treated with intravesical
hyaluronan therapy from 2001 to 2003 were asked to rate their
present status of bladder symptoms on a visual analog scale.
Results Forty-eight of 70 patients responded after a mean
follow-up of 4.9 years. The average initial VAS score of 8.15
had been reduced to 2.71 after therapy and further to 2.14
5 years later. Fifty percent of patients (24/48) reported
complete bladder symptom remission at 5 years follow-up
without any additional therapy; 41.7% (20/48) with symptom
recurrence was improved with hyaluronan maintenance
therapy. No improvement was reported by four patients.
Conclusions Besides a high rate of acute symptom remis-
sion, intravesical hyaluronan also shows long-term efficacy
in a considerable number of BPS/IC patients.
Keywords Bladder pain syndrome .GAG substitution .
Hyaluronan .Hyaluronic acid .Inst illation therapy .
Interstitial cystitis
Introduction
Glycosaminoglycan (GAG) substitution therapy is one of the
most popular regimens for treatment of BPS/IC. Response rates
between 30% and 80% have been described with intravesical
administration of various substances like hyaluronan, pentosan
polysulfate (PPS), heparin; chondroitin sulfate, and DMSO.
Most of these studies were uncontrolled and short-term
observational. Despite acceptable response rates in these
reports, no significant advantage over placebo was found when
study settings were controlled [1–8].
One of the largest published series on intravesical hyalur-
onan therapy in BPS/IC from our institution showed >80%
symptom response rate 6 months after treatment in a therapy-
naïve group of patients selected by a positive modified
potassium test [9]. Since long-term follow-up data for patients
after instillation therapy are only addressed in a single study
from Kallestrup for a small patient cohort [10], we assessed
the present bladder symptom status of our patients 5 years
after instillation therapy.
Materials and methods
Seventy female patients with the diagnosis of BPS/IC
conforming to present ESSIC criteria (“the diagnosis of
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
confusable diseases as the cause of the symptoms”) who
had been treated with intravesical hyaluronan 40 mg in
50 cm
3
phosphate-buffered saline (Cystistat®, Bioniche,
Galway, Ireland) in the years 2001–2003, were reevaluated
with a questionnaire by mail. Patients were selected for
P. F. Engelhardt (*):N. Morakis :C. R. Riedl
Department of Urology, Landesklinikum Thermenregion Baden,
Wimmergasse 19,
2500 Baden, Austria
e-mail: paul.engelhardt@aon.at
L. K. Daha
Department of Urology, Krankenhaus Hietzing,
Vienna, Austria
B. Esterbauer
Urologic Clinic, Paracelsus University of Medicine,
Salzburg, Austria
Int Urogynecol J
DOI 10.1007/s00192-010-1294-y

hyaluronan therapy by a positive modified potassium test, i.
e., patients had to show a >30% reduction of maximal
bladder capacity in a consecutive instillation of saline
(NaCl 0.9%) and KCl 0.2 M as described by Daha et al.
[11]. These patients received weekly hyaluronan instilla-
tions until symptoms resolved as to patients judgement or if
instillation therapy turned out to be ineffective after a
maximum of 10 instillations. Instillation therapy was only
performed in patients who were able to retain the
instillation for 2 h.
The questionnaire was identical to questionnaires before
and after instillation therapy as published before and asked
for:
1. The present status of global bladder symptoms (“Please
rate the presently perceived intensity of your bladder
symptoms”) by a visual analog scale (VAS, 0 to 10,
where 0 is no symptoms and 10 is intolerable bladder
symptoms)
2. Additional therapies within the last 5 years
3. And a global judgement of instillation therapy (“Would
you undergo instillation therapy again?”and “Would
you recommend instillation therapy to other patients?”)
Improvement was defined as a VAS score reduction of
>2 points following therapy.
Statistical analysis was performed by Friedman ANOVA
and Kendall Coefficient of Concordance Test (p<0.05) and
by Randomization Test (p<0.05).
Results
The response rate to the questionnaire was 68.5% (48 of 70
patients). Patients’demographics are shown in Table 1.
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 this
patients group had been 6.1 years (0.5–12 years) before
initiation of treatment. The average number of instillations
was 11.8 (8–25).
Tab le 2shows the long-term outcome of hyaluronan
instillation therapy: 50% of patients (24/48) were free of
bladder symptoms after hyaluronan instillation therapy for
the whole observation period; their VAS was 1.4 at present
follow-up. While only 8.3% (4/48) of patients did not
experience any benefit from hyaluronan therapy, bladder
symptoms recurred during the first year after initial
improvement in 20/48 patients (41.7%). These recurrences
were treated with another course of weekly hyaluronan
instillations followed by monthly maintenance therapy in
12 patients, supported by a daily dose of oral pentosanpo-
lysulfate in another eight patients. The VAS at present
follow-up for this group with maintenance treatment was
2.4. The four nonresponders were also treated with a
combination of intravesical hyaluronan and oral PPS to
maximize GAG substitution therapy, and later with
alternative therapies like amitryptilin, however, without
success.
VAS scores before therapy and throughout follow-up
are shown in Tables 3and 4as well as Fig. 1.The
average initial VAS score for all patients was 8.15 (SD ±
1.67), decreased to 2.71 (SD± 1.96) immediately after
hyaluronan therapy, stayed stable at 6 months post
instillation therapy with an average 2.7 (SD ± 2.1), and
showedafurtherreductionto2.14(SD±2.31)5years
later. VAS score reduction after therapy was statistically
significant (p=0.0001).
A VAS score reduction of >2 was observed in 85.4% of
patients (41/48), whereas 6.25% (3/48) showed a reduction
<2%, and 8.3% (4/48) reported no improvement. While
initial VAS scores were similar for three treatment groups
(group 1: single course of intravesical hyaluronan with
permanent remission, group 2: repeat course and mainte-
nance of hyaluronan therapy, group 3: maintenance with
intravesical hyaluronan and oral PPS), group 1 had the
lowest 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 four
nonresponders.
No statistical correlation was found between patient age
or duration of BPS/IC symptoms and the grade of symptom
remission.
Discussion
The efficacy of hyaluronan is based on several mechanisms
that aim on the urothelial function disorder present in BPS/IC:
on one side, hyaluronan reinforces the urine-tissue barrier by
integration in the GAG layer on the luminal surface and the
base of urothelial cells; on the other side, unique antiin-
flammatory mechanisms have been identified, like inhibition
of leukocyte migration, adherence of immune complexes, and
Mean age 48.3 years (17–81)
Mean follow up time 4.9 years (4–6.8)
Mean disease duration before hyaluronan therapy 6.1 years (0.5–12)
Total numbers of hyaluronan instillations mean 11.8 (8–25)
Questionnaire response rate 68.5% (48/70)
Table 1 Hyaluronan instillation
history
Int Urogynecol J

binding to specific receptors (I-CAM 1, CD 44) involved in
the inflammatory process [12–14].
The present report is the first that assesses treatment
results 5 years after hyaluronan instillation therapy. Even
with the setback of an uncontrolled study and a nonre-
sponse rate to the questionnaire of 31.5% which reduces the
response rate in an intention-to-treat analysis to 34%, there
are several important conclusions that can be drawn from
the data:
1. Intravesical hyaluronan therapy may lead to persistent
symptom remission in a selected group of BPS/IC
patients. In conventional terms, these patients, 50% in
the present survey, may be regarded as cured from their
disease. However, late recurrences surpassing the
observation period cannot be excluded.
2. Part of the patients with symptom remission after
intravesical hyaluronan therapy relapses early within
the first year; however, treatment response was main-
tained by continuation of instillation therapy through-
out the whole observation period. In some patients, oral
PPS was added to the GAG substitution regimen, if
either they were not able to regularly come to
instillations for an extended period of time or if
hyaluronan therapy alone did not improve symptoms
to patients expectations. (n=12)
3. Hyaluronan long-term therapy has no adverse effects
and can be administered over years without disadvan-
tage for the patients.
The only comparable long-term results were reported by
Kallestrup [10]: in this series, 20 BPS/IC patients had been
treated with intravesical hyaluronan for 3 months (four
weekly and two monthly instillations) and were followed
for 3 years. After the initial 3 months of treatment, 65% of
patients reported symptom improvement (nocturia was
reduced 40%, pain 30%) and continued monthly hyalur-
onan instillations up to 3 years. About 50% of these
patients stopped therapy within this 3 years period because
of complete symptom remission, while the other 50% still
kept monthly maintenance therapy and were judged as
partial responders. These data are confirmed by the present
report.
Similar results as in the present study have not been
reported for other GAG substituents. Response rates after
initial instillation therapy were 45% for chondroitin sulfate,
56% for heparin, and 44% for PPS [5–7]. Long-term results
do not exist for these substances.
The high response rate in the present study may be a
consequence of patient selection and standardization of
instillation therapy:
1. The modified potassium test is believed to indicate a
disorder at the urine-tissue barrier. Only patients with a
positive test were included in the present study. This set
of patient responds better to GAG substitution therapy,
whereas potassium negative patients show a very low
response rate of about 20% [15–17]. Only recently, it
was shown that successful hyaluronan instillation
therapy with symptom remission reverses positive
potassium sensitivity to normal [18].
2. Patients were treatment-naive for BPS/IC, i.e. hyaluronan
therapy was their first disease-specific therapy. Patients
Table 2 Long-term follow-up after initial hyaluronan instillation therapy
Stable symptom improvement after primary therapy without any further therapy during follow up 50% (24/48 pat.)
Stable symptom improvement with intermittent hyaluronan instillation therapy during follow up 25% (12/48 pat.)
Stable symptom improvement with intermittent hyaluronan instillation therapy and oral PPS during follow up 16.7% (8/48 pat.)
VAS Scores (mean ± SD (minimum–maximum))
Pretreatment 8.15 ± 1.7 (4.0–10.0)
After instillation therapy 2.71 ± 1.96 (0.0–8.0)
6 months after therapy 2.70 ± 2.1 (0.0–8.0)
5 years after therapy 2.14 ± 2.31 (0.0–8.0)
VAS reduction 5 years after initial hyaluronan therapy
Improvement >2 VAS units 41 (85.4%)
Improvement <2 VAS units 3 (6.25%)
Unchanged 4 (8.35%)
Absolute VAS values at 5 years follow-up
VAS 0 (asymptomatic) 16 (33.3%)
VA S 1 –2 (mild symptoms, no subjective need for therapy) 14 (29.2%)
VAS >2 (moderate symptoms, request for therapy) 18 (37.5%)
Table 3 VAS symptom
scores throughout the
observation period
Int Urogynecol J

with a number of unsuccessful preceding treatments
represent a negative selection of possibly advanced or
neuropathic disease, which usually does not respond to
GAG substitution therapy.
3. The average number of instillations was almost 12 in
the present series and, thus, appreciably higher than in
the reports of other investigators that normally used a
schedule of four weekly followed by two to four
monthly instillations.
4. To be eligible for the protocol, patients had to be able
to retain the hyaluronan instillation for at least 2 h.
Shorter bladder contact times show less efficacy. Thus,
patients with low bladder capacities (and possibly more
advanced disease) were not included. Anti-infective
prophylaxis with nitrofurantoin 50 mg on instillation
days prevented bladder infections from catheterism,
which counteract the beneficial effect of intravesical
hyaluronan.
5. The 8.3% of patients that did not respond to hyaluronan
instillation therapy stayed unimproved after 5 years, i.e.
also other therapies that were initiated during this
period did not influence symptomatology. This subset
of BPS/IC patients stays the “hard core”that needs to
be subject of future investigations.
In summary, besides a high rate of acute symptom
remission, intravesical hyaluronan also showed long-term
efficacy in a considerable number of BPS/IC patients in the
present study, which suggests that some patients may be
cured by this therapy. Patients with symptom recurrence
after instillation therapy have a high chance for symptom
remission with hyaluronan maintenance 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
No. patients (total 48) 24 12 12
Responders/Nonresponders 24/0 12/0 8 4
Initial VAS 8.9 9.0 8.0 8.0
VAS after therapy 2.9 2.5 2.5 8.0
Present VAS 1.4 2.4 4.1 8.0
CR complete remission, Ha hyualuronian, PPS pentosan polysulfate
Fig. 1 Box plot figure of VAS
symptom score during follow-up
Int Urogynecol J

Conflicts of interest Claus R. Riedl is the principal investigator for
controlled study on Hyaluronan in BPS/IC (CISTIC).
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