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ORIGINAL ARTICLE
Hyaluronan treatment of interstitial cystitis/painful bladder
syndrome
Claus R. Riedl & Paul F. Engelhardt & Kurosch L. Daha &
Nike Morakis & Heinz Pflüger
Received: 11 April 2007 / Accepted: 11 November 2007
#
International Urogynecology Journal 2007
Abstract The aim of this study is to evaluate the efficacy of
intravesical hyaluronan therapy in interstitial cystitis/painful
bladder syndrome (IC/PBS). One hundred twenty-six
patients with IC/PBS and an average disease duration of
6.1 years were treated with weekly instillations of a 50-cm
3
phosphate-buffered saline solution containing 40 mg sodium
hyaluronate. To be eligible for hyaluronan treatment, a
positive modified potassium test was requested as a sign of
aurine–tissue barrier disorder. Data were obtained by a
visual analogue scale (VAS) questionnaire rating from 0 to
10 that asked for global bladder symptoms before and after
therapy. Additional questions evaluated the therapeutic
impact on quality of life. A positive and durable impact of
hyaluronan therapy on IC/PBS symptoms was observed—
103 (85%) of the patients reported symptom improvement
(≥2 VAS units). The mean initial VAS score of 8.5
decreased to 3.5 after therapy (p<0.0001). Out of 121
patients, 67 (55%) rem ained with no or minimal bladder
symptoms after therapy (VAS 0–2). The majority (101,
84%) reported significant improvement of their quality of
life. Intravesical therapy had to be initiated again with good
success in 43 patients (34.5%) as symptoms recurred after
discontinuation of treatment, while the rest stayed free of
symptoms for up to 5 years. In general, hyaluronan therapy
was well tolerated and, with the exception of mild irritative
symptoms, no adverse reactions were reported for a total of
1,521 instillations. Timely hyaluronan instillation therapy
may lead to complete symptom remission or even cure in
part of the IC/PBS patients, while some responders need
continuous intravesical therapy. The present results suggest
that selection of patients for hyalu ronan the rapy by
potassium testing improves the outcome of intravesical
therapy with a response rate of >80%.
Keywords Interstitial cystitis
.
Hyaluronan
.
Instillation therapy
.
GAG substitution
.
Hyaluronic acid
Introduction
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a
chronic inflammatory disease of the bladder wall that is
characterised by bladder pain and a variety of voiding
symptoms [1]. The multifactorial aetiology and obscure
pathogenesis as well as too rigid and restrictive diagnostic
criteria in the past are responsible for the fact that controlled
studies on IC/PBS therapies are rare and mostly include only
small numbers of patients that are heterogeneous as to their
symptoms and duration of disease. Thus, present therapeutic
recommendations are mainly based on empiric data [2].
One of the favourite pathophysiologic hypotheses for IC/
PBS proposed throughout the last decades is based on a
disorder of the urine–tissue barrier [3, 4]—disturbanc e of
the balanc e between hyperosmolaric urine and the physio-
logic tissue compartment and penetration of toxic urinary
compounds into the bladder wall (“urothelial hyperperme-
ability”), as also seen in acute cystitis, induce urgency,
frequency and pain. As an essential contributor to the
protective barrier at the urothelial level, glycosaminogly-
cans (GAGs) have played an important role in pathophys-
Int Urogynecol J
DOI 10.1007/s00192-007-0515-5
C. R. Riedl (*)
:
P. F. Engelhardt
:
N. Morakis
Department of Urology, Landesklinikum Thermenregion,
Wimmergasse 19,
2500 Baden, Austria
e-mail: claus.riedl@baden.lknoe.at
K. L. Daha
:
H. Pflüger
Department of Urology and Ludwig Boltzmann
Institute for Andrology and Urology,
Vienna, Austria
iologic, diagnostic and therapeutic IC/PBS concepts. GAGs
are long, linear polysaccharide compounds synthesized by
urothelial cells and associated to the urothelial cell
membrane, where they reinforce the surface and form an
additional permeability barrier by water binding and
consecutive volume increase. GAGs play a major role in
urothelial homeostasis by reduction of the direct contact of
urine with the urothelium [5, 6]. GAG deficiency has been
suggested as a primary cause not only of IC/PBS but also of
ulcerative colitis and Crohn’s disease [7].
Although reports about the demonstrability of GAG
deficiency as well as the proposed urothelial hyperperme-
ability in IC/PBS patients have been controversial, GAG
substitution concepts have obtained a predominant position in
IC/PBS therapy with appreciable response rates [8–13]. In a
recent survey among European IC/PBS experts, GAG
substitution was rated as first-line therapy (personal commu-
nication, third meeting of the European Society for Studies in
Interstitial Cystitis, Baden, Austria, June 16–18, 2005).
At present, three GAG substituents (heparin, hyaluronan—
the correct term for the therapeutic drug derived from
hyaluronic acid which is too acidic for intravesical use—and
chondroitin sulphate) and one heparinoid (pentosan poly-
sulphate (PPS)) are available for substitution therapy. For oral
PPS, efficacy has been proven despite conflicting results [10].
Reports on the therapeutic use of chondroitin sulphate are
sparse [12, 13].
For intravesical hyaluronan therapy, several uncontrolled
studies have shown excellent efficacy in IC/PBS with
response rates up to 70% [9, 14, 15], as well as in other
chronic inflammatory bladder diseases such as radiation
and recurrent bacterial cystitis [16, 17]. However, these
studies include only small numbers of patients and, with
one exception, the follow-up is less than 1 year. Encour-
aged by the promising results of intravesical hyaluronan
therapy, we offered this therapy as a first-line treatment to
our IC/PBS patients and evaluated the outcome by means
of a standardised questionnaire.
Materials and methods
Since year 2000, 121 female pa tients with confirmed
diagnosis of IC/PBS and an average disease duration of
6.1 years (0.5–12) were treated at two institutions with weekly
instillations of a 50-cm
3
phosphate-buffered saline solution
containing 40 mg sodium hyaluronate (Cystistat®, Bioniche
Pharma Group, Inverin, Co. Galway, Ireland). To be eligible
for hyaluronan treatment, a positive modified potassium test
was requested, i.e. patients had to show a >30% reduction
(difference) of maximal bladder capacity (test) with consec-
utive instillation of saline and 0.2 M KCl (as described by
Daha et al. [18]) prior to initiation of hyaluronan therapy.
Instillation therapy was only performed in patients who
were able to retain the instillati ons for a minimum of 2 h.
All patients were instructed to take 50 mg nitrofurantoin on
instillation days to prevent urinary tract infection from
catheterism. All instillations were performed with hydro-
philic 10 F Foley catheters. Instillations were continued
until patients were either free of IC/PBS symptoms or until
symptoms had significantly improved to their satisfaction
and no more instillations were requested. Instillations were
discontinued in the absence of any beneficial effect reported
by patie nts after a maximum of ten instillations.
Data were obtained by means of a questionnaire which
was mailed to the patients at a mean 6.5 months after their
last hyaluronan instillation. The questionnaire asked for
assessment of global-bladder- or IC-related symptoms at
the time of the last instillation and at the time of completion
of the questionnaire, using a visual analogue scale (VAS)
rating from 0 to 10 (0 = no symptoms; 10 = maximal
symptoms), as compared to pretreatment symptoms that
were recorded before initiation of therapy. Additional
questions evaluated the overall impact of instillation
therapy on quality of life and if patients would decide to
undergo instillation therapy again.
In a statistical analysis of data, mean VAS symptom
scores were determined for the pretreatment and posttreat-
ment as well as follow-up periods, and values were
compared using the Wilcoxon signed-rank test.
Results
The mean age of the 121 IC/PBS patients was 49.4 years
(17–83 years). The mean maximal bladder capacity with the
modified potassium test was 322.5 cm
3
(28–700) with
saline and 190.8 cm
3
(5–450) with 0.2 M KCl. The mean
difference was 41%. The time of completion of the study
questionnaire was an average of 6.5 months after the last
instillation. The average numbe r of instillations for all
patients was 12.2 (SD±7.4; Table 1).
A positive and durable impact of hyaluronan therapy on
IC/PBS symptoms w as apparent in the assessme nt of
pretreatment and posttreatment VAS scores (Table 2)—
initial VAS symptom scores were high with a mean score of
8.5 (4–10), which means that most patients had severe,
close to maximal bladder symptoms. Following hyaluronan
instillation therapy, 85% of the patients reported symptom
improvement ≥2 VAS units, and the observed decrease of
the mean VAS score to 3.5 (0–10) was significant (p<
0.0001). At the time of questionnaire completion, the VAS
score improvement remained stable at 3.5 (0–10). The
mean decrease of VAS scores from pretreatment to post-
instillation was −5.0 ( −59%). Nineteen patients reported a
VAS score of 0 at the end of instillation therapy, and a total
Int Urogynecol J
of 67/121 patients (55%) remained with no or minimal
bladder symptoms (VAS≤ 3) after therapy.
There was a high level of satisfaction with hyaluronan
therapy amongst patients. The majority (84%) reported that
their quality of life had improved significantly with intra-
vesical therapy and a similar number (86%) would agree to
repeat hyaluronan instillations in the future if necessary.
Although the initial hyaluronan instillation regimen was
continued until IC/PBS symptoms had either disappeared or
were significantly improved, intravesical therapy had to be
initiated again in 34.5% of the patients as symptoms
recurred after discontinuation of treatment (Table 1). By
this regimen, the beneficial therapeutic effect was main-
tained.
In general, hyaluronan therapy was well tolerated and,
with the exception of mild irritative symptoms consequent to
catheterisation and cystitis episodes when anti-infective
prophylaxis was not performed, no adverse reactions were
reported over the whole treatment period and a total of 1,521
instillations.
Discussion
The response rate of 85% in the present series is remarkably
higher than those reported by Morales et al. (71%) [9] and
Kallestrup et al. (65%) [15] and may be a consequence of
treatment procedures and/or patient selection. Special
treatment stand ards were: (1) instillation times of at least
2 h, excluding all patients that were not able to retain
hyaluronan long enough to exert its beneficial local effects
(which also means that patients with very low functional
capacities <50 cm
3
are no candidates for instillation
therapy) and (2) anti-infective prophylaxis that prevents
catheter-induced cystitis and, thus, symptom deterioration
in a patient group prone to urinary tract infection.
Patient selection by potassium testing may be an
important reason for the high response rate of the present
series. The modified potassium test [18] was chosen in the
present series to identify patients with a presumptive defect
at the urine–tissue barrier that might be restored by GAG
substitution therapy, while patients without this defect are
less likely to respond to GAG substitution. This selection
principle is supported by several reports demonstrating that
the response to GAG substit ution therapy is significantly
lower in potas sium-negative patients than in potassium-
positive patients [19, 20], a finding that conforms to our
personal experience.
Although the mean duration of IC/PBS-specific bladder
symptoms was 6.1 years in the present series, the diagnosis
of IC/PBS had been suggested in <20% of patients prior to
presentation at our department, and no IC/PBS-specific
therapy had been initiated before. Thus, patients in the
present series can be regarded as IC/PBS-therapy-naïve
patients, which may explain the excellent outcome that
stands in contrast to the study of Whitmor e et al. (personal
communication and presentation, first annual meeting of
the Multinational Interstitial Cystitis Association, Rome,
Italy, Sept. 2004), who failed to show any difference
between placebo and hyaluronan in patients who had
undergone a multitude of unsuccessful therapies before
and had not been subject to the selection and treatment
standards of the present series as outlined before.
Most interestingly and according to the report of
Kallestrup et al. [15], a part of the IC/PBS patients treated
Table 2 VAS symptom scores
Parameter Hyaluronan-treated patients
(n=121)
VAS scores (mean±SD (minimum−maximum))
Pretreatment 8.5±1.7 (4.0−10.0)
Posttreatment 3.5±2.7 (0.0−10.0)
Follow-up
a
3.5±2.7 (0.0−10.0)
Mean VAS score changes (mean±SD (minimum−maximum))
Pretreatment to posttreatment −5.0±2.8
b
(−10.0− 0.0)
Posttreatment to follow-up +0.0±2.3
Pretreatment to follow-up −5±2.9 (−10.0−1.0)
Patient changes between pretreatment and follow-up
Improved≥ 2 VAS units 103 (85%)
Improved<2 VAS units 6 (5%)
Unchanged 12 (10%)
VAS Visual analogue scale, SD standard deviation
a
Follow-up assessment refers to the VAS score recorded at the time of
completion of the questionnaire
b
Pretreatment VAS score was significantly different (p<0.0001) from
posttreatment and follow-up scores; scores between posttreatment and
follow-up were not significantly different (p=0.7036)
Table 1 Hyaluronan instillation history and patient impact
Parameter Hyaluronan-treated patients (n=121)
Follow-up time after last instillation (months)
Mean 6.5
Minimum−maximum 0.0−23.0
Total number of instillations
Mean±SD 12.2±7.4
Minimum−maximum 1.0−40.0
Reinstitution of hyaluronan therapy to maintain
therapeutic effect—42 (34.5%)
Patient impact
Did therapy improve QoL?
Yes 101 (84%)
No 20 (16%)
Would agree to instillation therapy in the future?
Yes 103 (85%)
No 18 (15%)
SD Standard deviation, QoL quality of life
Int Urogynecol J
with intravesical hyaluronan seems to be cured, because they
do not need additional treatment after instillation therapy. In
the present series, only about one third (34.5%) of the 85%
of patients with symptom remission or improvement had to
restart instillation therapy when symptoms recurred. This
means that about 50% of the patients initially treated with
intravesical hyaluronan did not need additional therapy for a
follow-up of up to 5 years. Without an evidenced explana-
tion for this phenomenon, it may be hypothesised that, in
part of IC/PBS patients, timely GAG substitution may
restore the urothelial or GAG defect, while in case of
continuous damage to the urine–tissue barrier, GAG substi-
tution therapy has either to be administered continuously or
stays ineffective. This theory is supported by the observation
that potassium-positive patients with symptom remission
after GAG substitution therapy turn potassium-negative,
which suggests normalisation of the urine–tissue barrier
disorder, while non-responders stay potassium-positive after
therapy [21, 22].
While side effects from hyaluronan as a biologic substance
normally found in the bladder and other tissues are very
improbable, the biochemical properties sugges t superior
efficacy compared to other GAG substituents. In contrast to
other GAGs, hyaluronan does not appear to be integrated into
cell membrane proteoglycans, but binds to a number of
receptors expressed by urothelial cells (intracellular adhesion
molecule (ICAM-1), receptor for hyaluronan mediated
motility, cluster of differentiation 44 (CD44)), and may, thus,
become part of the urine–tissue barrier when substituted by
instillation [6, 23]. Other exogenous GAG species like
heparin or chondroitin sulphate need to be integrated in cell
membrane proteoglycans by active synthesis in an energy-
consuming intracellular process (that may be impossible in
damaged urothelial cells) to exert its barrier properties. The
larger size of the hyaluronan molecules and the higher
binding capacity of water molecules compared to other GAG
substitutes suggest an improved barrier function. In addition,
hyaluronan is predominantly found at the basal cell
membrane, where reinforcement of the urine–tissue barrier
is more consistent in contrast to superficially substituted
GAGs that may be washed out with the urine. An even more
important protective mechanism may be the binding of
hyaluronan to cellular receptors that play a key role in
inflammatory cascades (ICAM-1, CD44) [24]. This may
provide an explanation for the strong anti-inflammatory
effect of hyaluronan. Whether these biochemical properties
or other mechanisms like the suppression of urothelial ATP-
release [25] or the desactivation of the inflammatio n-
mediating nuclear factor κB[26] or even not yet defined
processes are responsible for the superior reported response
rates of hyaluronan compared to other GAG substituents is
still unclear.
The summary of published studies in Table 3 demon-
strates the efficacy of GAG substitution therapies, suggest-
ing that response rates for the various substituents and
regimens may differ. Selection of patients for GAG
substitution therapy seems crucial, and lower response rates
may only be consequent to inclusion of patients without a
urine–tissue barrier disorder.
The 15% no n-responders to intravesical hyaluronan
therapy in the present series, together with those patients
who did not fulfill the enrollment criteria of a positive
potassium test, stay as the challenging “core” of IC/PBS
patients. It is important to find more treatment algorithms,
similar to potassium testing for GAG substitution therapy,
to offer and individually adapt the most promising therapies
from a comprehensive repertoire and spare patients the
troublesome course of therapeutic trial and error.
Being aware that the lack of control is a considerable
setback in the present study but encouraged by the favourable
findings in a challenging disease, a multinational controlled
study on hyaluronan therapy is presently performed. The
present findings give hope to IC/PBS patients that are
confronted with the diagnosis of a chronic and incurable
disease, because they suggest that a considerable number has
a high chance of symptom improvement or even cure.
Table 3 Published studies on glycosaminoglycan substitution therapy
Author GAG substituent Number
of patients
Study design Response
rate (%)
Time
frame
Hwang, 1997 [10] Oral pentosan polysulphate 398 Placebo-controlled (meta-analysis) 28–54 3 months
Sant, 2003 [27] Oral pentosan polysulphate 121 Controlled (vs. hydroxyzine) 34 6 months
Bade, 1997 [28] Intravesical pentosan polysulphate 20 Controlled (vs. placebo) 44 18 months
Steinhoff, 2002 [12] Chondroitin sulphate 18 Uncontrolled 44.4 13 months
Parsons, 1994 [11] Heparin 48 Uncontrolled 56 12 months
Morales, 1996 [9] Hyaluronic acid 25 Uncontrolled 71 6 months
Kallestrup, 2005 [15] Hyaluronic acid 20 Uncontrolled 65 3 years
Int Urogynecol J
Conflicts of interest None.
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