Interstitial Cystitis: An Unsolved Enigma Mini-Review Dimitrios-Anestis Moutzouris* and Matthew E. Falagas

Transcription

CJASN ePress. Published on October 1, 2009 as doi: 10.2215/CJN.02000309
Mini-Review
Interstitial Cystitis: An Unsolved Enigma
Dimitrios-Anestis Moutzouris* and Matthew E. Falagas†‡
*Department of Nephrology, “Evangelismos” General Hospital, Athens, Greece; †Alfa Institute of Biomedical Sciences
(AIBS), Athens, Greece; ‡Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts
Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic disease of unknown etiology characterized by vague bladder
pain and nonspecific urinary symptoms, such as urgency and frequency. Although it was initially considered to be a rare condition,
its prevalence has significantly increased, possibly because of different definitions used and greater physician awareness. Because
of the multiple diagnostic criteria used, there is significant variation in its prevalence. In addition, there is often a delay in the
diagnosis of PBS/IC. It affects predominantly women of middle age, and it significantly decreases quality of life. Diagnosis of
PBS/IC is mainly a diagnosis of exclusion; there are no characteristic symptoms or pathognomonic findings. Therefore, it is
important to rule out diseases that have a similar clinical picture (i.e., urinary infections, bladder carcinoma) but definite therapies
and worse prognosis if left untreated. PBS/IC management suffers from lack of evidence; many therapies are empiric or based on
small studies and case series. Treatment includes supportive therapies (psychosocial, behavioral, physical), oral treatments, and
intravesical treatments, whereas other more invasive treatments such as electric neuromodulation and reconstructive surgery are
reserved for refractory cases. Physicians should always keep in mind the diagnosis of PBS/IC in patients presenting with chronic
urinary symptoms after excluding other more common diseases.
Clin J Am Soc Nephrol 4: ●●●–●●●, 2009. doi: 10.2215/CJN.02000309
lthough painful bladder syndrome/interstitial cystitis (PBS/IC) was first described in 1887 by Skene and
despite numerous conferences of professionals involved in PBS/IC diagnosis, efforts to establish a universally
accepted definition have been futile (1). Nevertheless, its prevalence is increasing, possibly because of greater physician
awareness of PBS/IC or because of different definitions or
diagnostic criteria applied in recent studies.
A
zations adopted the ICS definition with minor modifications
(1). In addition, the European Society for the Study of PBS/IC
(ESSIC) decided later to rename PBS as bladder pain syndrome
(BPS), proposing use of findings from cystoscopy and hydrodistention for patient staging (5). Some authors suggest that
PBS/IC represents at least two different entities, the classic and
the nonulcer; the latter is associated with younger age at diagnosis and milder reduction in bladder capacity.
Definition
Epidemiology
The National Institute of Diabetes, Digestive and Diseases of
the Kidney (NIDDK) suggested in 1988 the use of diagnostic
criteria for enrollment in PBS/IC studies (2,3), including bladder pain or urinary urgency, glomerulations or Hunner’s ulcers
during cystoscopy or hydrodistention, and absence of other
pathologies (Table 1). In addition, it described minimum criteria regarding age, duration of symptoms, degree of frequency,
and nocturia. However, with the use of the NIDDK definition,
up to 60% of patients clinically diagnosed to have PBS/IC by
experienced clinicians were being missed (3).
The International Continence Society (ICS) proposed in 2002
the term “painful bladder syndrome.” It was defined as the
complaint of “suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and
nighttime frequency in the absence of proven infection or other
obvious pathology” (4). Several scientific meetings and organi-
Published online ahead of print. Publication date available at www.cjasn.org.
Correspondence: Dr. Matthew E. Falagas, Alfa Institute of Biomedical Sciences
(AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Phone: ⫹306946110000; Fax: ⫹30-2106839605; E-mail: [email protected]
Copyright © 2009 by the American Society of Nephrology
The prevalence of PBS/IC varies because of the several definitions and methods used to estimate it. Whereas in older
studies, PBS/IC seems to be relatively rare (6) (18.1/100,000
women and 10.6/100,000 men), recent studies report a higher
prevalence of 52 to 197/100,000 women and 40 to 70/100,000
men (7,8) when diagnosis is made by the physician. However,
prevalence is much higher when diagnosis is based on selfreport of previous PBS/IC diagnosis (501– 865/100,000 patients) (9); prevalence of PBS/IC symptoms is even higher
when estimated by the use of questionnaire without clinical
examination (10,11) (450 –11,200/100,000 patients). PBS/IC is
more common in women, with a female/male ratio that ranges
from 5:1 to 10:1 (12). Median age at diagnosis is 42 to 46 yr old
(13), whereas men are diagnosed at a younger age (7).
Pathophysiology
Although PBS/IC underlying pathophysiology is incompletely understood, it involves primarily urothelial permeability changes, along with mast cell activation and neurogenic
inflammation (14) (Figure 1). In PBS/IC, damage of the protective bladder lining leads to impaired urothelial cell barrier
function. Consequently, urinary solutes penetrate the epitheISSN: 1555-9041/411–0001
2
Clin J Am Soc Nephrol 4: ●●●–●●●, 2009
Clinical Journal of the American Society of Nephrology
Table 1. National Institute for Diabetes and Diseases of
the Kidney criteria
For PBS/IC diagnosis to be made, patients should have:
1. Bladder pain or urinary urgency
2. Glomerulations or Hunner’s ulcers on cystoscopy/
hydrodistention
3. None of the following:
Awake cystometric capacity ⬎350 ml using a fill
rate of 30-100 ml/min,
Absence of intense urge to void at 100 ml gas or
150 ml liquid,
Involuntary detrusor contractions on cystometry,
Urinary frequency ⬍8 voids/d,
Absence of nocturia,
Duration of symptoms ⬍9 mo,
Age ⬍18 yr,
Cystitis (bacterial, chemical, post-irradiation),
prostatitis, vulvitis (herpes) or vaginitis,
Cancer (bladder, uterine, cervical, vaginal or
urethral),
Bladder or lower ureteral calculi
Urethral diverticulum
Adapted from Reference 107.
lium and activate sensory nerve endings, leading to pain and
inflammation (15). Consistent with this theory, bladder epithelial cells in PBS/IC patients are shown to produce anti-proliferative factor (APF) (16), which may further contribute to the
impaired urothelial cell barrier. In addition, urothelial cells
from PBS/IC patients fail to release prostaglandin E2, which is
crucial for the protection and repair of the urothelium (17).
Other bladder epithelial abnormalities reported in PBS/IC include abnormal cellular architecture on electron microscopy
(18) and abnormal uroplakin expression assessed by reversetranscriptase PCR (19). Mast cell may play a central role in
PBS/IC pathophysiology: patients not only have increased
number of mast cells but also ⬎70% of them are activated versus
10% in healthy controls (20). Moreover, substances that are
indicative of mast cell activation such as IL-6, histamine, and
tryptase are increased in the urine of PBS/IC patients (17).
Interestingly, Tamm-Horsfall protein concentration in the urine
of PBS/IC patients may not differ from controls, but it is
qualitatively different containing less sialic acid (21); this altered protein may thus be involved in PBS/IC pathogenesis.
Neurogenic upregulation may also play a role in the pathogenesis of PBS/IC. The purinergic pathway has been shown to
be upregulated in urothelial cells from PBS/IC patients (22),
with the neural upregulation occurring both peripherally and
centrally (23). However, it is undetermined whether the neurogenic inflammation that characterizes PBS/IC is the cause or
the result of other previous unknown events.
PBS/IC could result from different environmental triggers in
a genetically susceptible individual (24 –26); this approach may
explain its increased prevalence among first-degree relatives
and monozygotic twins pairs. In this respect, PBS/IC could be
considered a spectrum of clinical phenomena in a genetically
susceptible individual, where an environmental trigger (such as
trauma or infection) provides the “second hit,” leading to an
uncontrolled inflammatory response.
Clinical Presentation
Clinical picture can be variable (27). PBS/IC often has insidious onset and remains undiagnosed for years, because not all
of the initial symptoms appear simultaneously but rather
present gradually. Symptoms include pain (considered as essential diagnostic criterion by all classification schemes), nocturia, urinary frequency, and urgency. Early in the disease,
symptoms may be mild and intermittent, but they tend to
become constant and severe over time (27). Frequency is a
common clinical presentation, followed by urgency and pain.
Pain can initially present as discomfort, burning, or pressure
sensation that evolves to severe pain. It is usually localized to
the suprapubic area; however, it is often reported in the lower
abdomen, urethra, vaginal area, scrotum, and rectum. PBS/IC
patients tend to void frequently to relieve pain (28); in contrast,
voiding to avoid urine leakage is typical in overactive bladder
syndrome (OAB), where urgency is the main symptom. Although absence of nocturia was initially considered inconsistent with PBS/IC diagnosis, it is now known that it can appear
later in the progress of the disease (2).
PBS/IC may present with flares lasting for several days and
remissions. Beverages containing biogenic amines, caffeine,
smoking, stress, allergies, and sexual activity are considered
precipitating factors (20,29). In addition, women report exacerbation of symptoms during the premenstrual week (29). Pain is
associated with sexual activity, leading to severe sexual dysfunction and poor quality of life (30); dyspareunia is a common
finding in PBS/IC patients. In addition, women with PBS/IC
have significantly more hysterectomies and other pelvic surgeries in comparison with age-matched controls (31); most of
them are done before PBS/IC diagnosis. However, it is unclear
whether these operations were performed because of pelvic
pain related to undiagnosed PBS/IC or the surgery itself contributed to chronic pelvic pain.
Several systemic and autoimmune conditions are more frequent in PBS/IC patients than the general population (32):
irritable bowel syndrome and systemic lupus erythematosus
are many folds more frequent in PBS/IC patients. In addition,
the increased prevalence of Sjögren disease, rheumatoid arthritis, and the presence of autoantibodies in PBS/IC patients
provide a possible background for an autoimmune underlying
pathophysiologic mechanism (33). Therefore, PBS/IC is often
considered a manifestation of a systemic disorder rather than a
specific organ disorder (34). The correlation of PBS/IC with
other unexplained physical symptoms and certain psychiatric
conditions (35) along with the absence of pathognomonic findings may further support this theory.
Diagnosis
Because there are no definitive diagnostic tests, PBS/IC remains a diagnosis of exclusion; the diagnostic steps aim to rule
out other diseases and overlapping syndromes.
Damage of the protective
bladder lining
Interstitial Cystitis
Numerous possible stimuli
(drugs, hormones, etc)
Upregulation of purinergic
pathway of urothelial cells
Mast cell activation and
degranulation
Peripheral and central neural
upregulation
3
Increased permeability to
urine solutes
Sensory nerve endings
activation
Chronic inflammatory bladder disorder
Figure 1. Proposed underlying pathophysiology in PBS/IC.
History and Physical Examination
A thorough history and physical examination is particularly
significant. Medical history should include history of symptoms (pain, nocturia, frequency, urgency), urinary infections,
pelvic surgeries, central nervous system, or autoimmune diseases. Symptoms of PBS/IC typically worsen during the premenstrual week in contrast with endometriosis (36). In addition, because PBS/IC occurs in flares, it is often misdiagnosed
as recurrent urinary tract infection (UTI) or prostatitis, with the
resolution incorrectly attributed to antibiotic therapy and not to
the disease’s natural pattern (37). There are no specific physical
findings in PBS/IC patients. However, a careful pelvic examination is essential to rule out vaginitis, vulvar lesions, urethral
diverticula, and pelvic floor dysfunction, whereas it may show
anterior vaginal wall and bladder base tenderness in women
with PBS/IC.
The O’Leary Sant symptom and problem index along with
the pelvic pain and urgency/frequency symptom scale are the
most commonly used surveys, which were developed for monitoring progress after treatment, but both have been used as
screening tools as well (38 – 40). A voiding diary can be extremely helpful for documenting voiding volume and frequency, not only for screening reasons but also for monitoring
response to treatment.
Laboratory Tests
There are no laboratory (urine or blood) tests that will identify PBS/IC. It is crucial, however, to rule out overlapping
diseases. Urinalysis and urine culture are essential to exclude
UTI. In presence of hematuria, and particularly in older patients with a history of smoking or with other risk factors for
bladder malignancy, urine cytology is significant. Cystoscopy
may be essential in severe cases of hematuria. In the quest for
noninvasive techniques for PBS/IC diagnosis, many urinary
biomarkers were tested: urinary histamine, tryptase, and others
were found to be elevated in a subgroup of PBS/IC patients but
they were not prospectively studied as a diagnostic tool. In
addition, urine IL-6 levels were increased only in newly diagnosed patients (20), and whether it could be used as a diagnos-
tic marker or as a predictor to response to treatment is still
controversial (41). Recently, anti-proliferative factor (APF) was
suggested as a candidate biomarker for PBS/IC diagnosis (42)
because it was shown to have increased activity in the bladders
of PBS/IC patients in comparison with asymptomatic controls.
Using proteomic techniques and quantitative biomarker analysis, Canter et al. (43) reported that PBS/IC patients had decreased concentration of uromodulin, kininogen, and increased
levels of inter-␣-trypsin inhibitory heavy chain H4 in their
urine; these substances could be used as biomarkers, but further studies are needed. Nitric oxide (NO), which is considered
a nonspecific marker of inflammation (44), was tested in a
recent study (45) as a possible diagnostic tool: NO levels in the
bladder were shown to correlate with the degree of inflammation and with the response to treatment, but the limitation of
this technique was that measurement of NO levels required
catheterization.
Other Diagnostic Procedures
Potassium Sensitivity Test. In the potassium sensitivity
test (PST), a potassium chloride solution and sterile water are
instilled sequentially directly in the bladder; increased pain
with the potassium solution is considered a positive test and
indicates epithelial dysfunction. However, the PST has its limitations: patients with chronic UTIs, bladder outlet obstruction,
or OAB may not respond to intravesical potassium (29). In
addition, the PST has 75% sensitivity and specificity and is not
recommended for diagnostic purposes because of its low prognostic value (20).
Urodynamic Studies. Urodynamic studies are optional,
and their use remains rather controversial. Nevertheless, they
can be helpful in excluding OAB and in evaluating bladder
dysfunction, especially in male patients.
Cystoscopy. Whereas cystoscopy was initially considered
mandatory for diagnosis (2,3,46), it is now performed at the
physician’s discretion. In the United States, it is performed
mainly when it is essential to rule out other pathology and
particularly underlying malignancy; however, in Europe, it is
4
considered to be important for diagnosis and for disease classification. In addition, it can be helpful in guiding treatment
(e.g., patients with reduced bladder capacity are unlikely to
benefit from oral pharmaceutical treatment). Hydrodistention
of the bladder, which consists of filling the bladder (under
general anesthesia) with normal saline or sterile water beyond
its normal capacity, can also be performed during cystoscopy.
With this technique, Hunner’s ulcers (patches) and glomerulations (pin-point petechial hemorrhage) can be more easily visualized. Glomerulations, once considered diagnostic of PBS/
IC, can also be found in other bladder pathologies and in
asymptomatic women (47). Hunner’s ulcers or Hunner’s lesions were originally described by Hunner (48) in 1915 and
initially considered as pathognomonic for PBS/IC. They represent positive signs for PBS/IC and designate a specific type of
the disease, not only cystoscopically, but also with reference to
histology, response to therapy, and prognosis (49). This type
was later defined as classic PBS/IC.
Biopsy. There are no specific findings in biopsies of patients with PBS/IC (47); therefore, biopsy in not essential for
diagnosis. However, it is indicated in a patient with suspected
PBS/IC, when specific bladder pathologies such as carcinoma,
dysplasia, or tuberculosis must be excluded. In addition, biopsy
findings can be useful in identifying subgroup of patients who
are most likely to benefit from specific treatments: patients with
mastocytosis or excessive eosinophils in bladder biopsy may be
more effectively treated with antihistamines (50).
Treatment
Because of the absence of definitive diagnostic tests and
standard clinical criteria, PBS/IC is a diagnosis of exclusion; as
a result, the design of randomized controlled trials (RCTs) for
its management is extremely difficult. Therefore, data regarding the efficacy of therapies are limited and often based on
uncontrolled studies or case series. Although ⬎180 different
treatments have been tried in PBS/IC, data are still inconclusive; only pentosan polysulfate sodium (PPS) was found to be
modestly beneficial (51). Three recent reviews focused on
PBS/IC treatment (20,51,52), whereas a recent well-designed
RCT gave promising results for therapy with intravesical alkalized lidocaine (53). Nevertheless, treatment of PBS/IC can be
divided to supportive (nonspecific) management and to specific therapeutic modalities that target the suggested underlying pathophysiology.
Supportive Therapies
Supportive therapies include general measures that can alleviate symptoms or prevent exacerbations. Psychosocial support
is significant because it is an essential part of any chronic pain
treatment. Because depression is not uncommon in PBS/IC
patients, referral to specialists is necessary if such a diagnosis is
suspected. Other comorbid diseases that are common in
PBS/IC patients (i.e., inflammatory bowel disease) should be
diagnosed and treated aggressively. All factors associated with
symptom exacerbation such as allergies, certain foods, and
body position should be avoided.
Behavioral therapy can be effective in improving PBS/IC
symptoms (54): avoidance of possible triggering factors or
timed voiding protocol leading to increased bladder capacity
are typical examples. Physical therapy by resolution of pain
and trigger points (55) can improve quality of life.
Specific Therapies
It remains an important goal to properly select patients with
PBS/IC for treatments based on individual patient characteristics. Currently, the most common stratification is based on
presence/absence of visible ulcers on cystoscopy. This is a
useful distinction because visible ulcers can be fulgurated (56).
There are many indicators of bladder inflammation in PBS/IC
(ulcers, NO, urine markers, bladder biopsy findings); however,
it is unknown which of these are most predictive of treatment
response (57). Specific therapies include intravesical, oral treatments, and other treatments, with the latter being used predominantly in refractory cases. Table 2 includes the most common PBS/IC treatments for which there is at least one RCT.
Other treatments for which there are no RCTs conducted are
shown in Table 3.
Oral Treatments
PPS is the only oral medication approved by the FDA for
treatment of PBS/IC. The approved dose is 100 mg three times
per day. Only trials for PPS-based therapy had enough numbers to allow pooled analysis of effect in a recent systematic
review, where PPS was showed to be beneficial with a relative
risk of 1.78 for patient-reported improvement in symptoms
(95% confidence intervals, 1.34 to 2.35) (51). However, the welldesigned NIDDK-supported trial (Interstitial Cystitis Clinical
Trial Group) failed to provide evidence for the efficacy of PPS
treatment in PBS/IC, although the study might be underpowered (58). In addition, increased doses of PPS (300 and 600 mg
daily) have not been associated with greater efficacy but with
more frequent adverse effects (59). PPS treatment within 6 mo
after PBS/IC diagnosis is associated with greater efficacy in
comparison with late treatment (60). However, administration
for a prolonged period may be required before clinical response
is noted, since oral treatment leads to low concentration in the
bladder; it has been shown that only 6% of PPS is excreted in
urine (61). The most commonly reported side effects include
nausea, diarrhea, headache, and alopecia (62).
Although evidence is limited, hydroxyzine is considered by
many urologists as a first-line treatment. Its anxiolytic and
anti-cholinergic effect along with its ability to inhibit bladder
inflammation may explain its efficacy (63). Dose starts at 25 mg
daily, given at bedtime, and should be slowly titrated to 50 to
75 mg. Prolonged administration (3 to 4 mo) may be needed
before any beneficial effect is shown; 40% of patients receiving
hydroxyzine for more than 3 mo reported improvement in an
open label study (64). However, the previously aforementioned
NIDDK-supported trial in a accurately designed RCT failed to
show the efficacy of hydroxyzine (58).
Amitriptyline, the oral tricyclic anti-depressant, is commonly
used in PBS/IC treatment. Mechanism of action includes regulation of pain through modulation of neuronal dysfunction.
The only placebo-RCT available showed amitriptyline to be
1988
2003
Hydroxyzine
Sant (58)
2005
Mayer (83)
DMSO intravesically
Perez-Marrero (81)
2000
Peeker (82)
2005
1997
BCG intravesical
Peters (84)
Cyclosporine
Sairanen (70)
2000
Antibiotics
Warren (75)
2001
2004
Amitriptyline
Van Ophoven (65)
Cimetidine
Thilagarajah (72)
Year
Treatment Study
121
33
64
36
265
21
33
50
50
No. of
Patients
24 wk
8 wk
24 wk
12 wk
6 wk
12 wk
6 wk
18 wk
16 wk
Duration
Response rate was 31% for
hydroxyzine vs. 20% for not
treated (P ⫽ 0.26) and 34% for PPS
vs. 18% for no PPS group (P ⫽
0.064)
Subjective improvement in 53% vs.
18% in placebo and objective
improvement in 93% vs. 35 in
placebo, P ⬍ 0.001.
Response (based on GRA) 75% for
Cya vs 19% for PPS (P ⬍ 0.001)
Symptoms improved (P ⬍ 0.001) in
treatment group. No histologic
change.
Response rate 21% (BCG) vs. 12%
(control) (P ⫽ 0.062), small
symptom improvement of
borderline SS
Decreased pain and urgency (only in
classic PBS/IC) in DMSO group
60 vs. 27% (in control) reported at
least moderate improvement (P ⫽
0.06)
No improvement in BCG group
Improvement (no SS) in pain,
urgency and overall in treatment
group
Mean symptom score decreased (P ⫽
0.005)
Pain and urgency intensity improved
(P ⬍ 0.001)
Results
Table 2. PBS/IC treatments for which there is at least one randomized controlled trial
Minor adverse events. No benefit provided
for the majority of patients.
Placebo (saline) may not be appropriate
because of effects of DMSO in smell and
taste. DMSO was given twice weekly.
More adverse effects in CyA group.
Randomized to BCG and DMSO group.
Crossover between treatments for
nonresponders. No clear wash out period
may have misclassified benefit.
Adverse effects more common in BCG
group without reaching SS
Similar adverse effects between groups
Treatment group had more adverse effects
(P ⫽ 0.009)
Anticholinergic side effects in 92% in
amitriptyline group
Comments
5
1990
1993
Parsons (112)
1987
PPS oral
Holm-Bentzen (109)
Mulholand (111)
2006
Oxygen hyperbaric
Van Ophoven (108)
1987
2000
Oxybutynin intravesically
Barbalias (85)
148
110
75
115
21
36
102
16
53
No. of
Patients
12 wk
12 wk
16 wk
16 wk
36 wk
18 wk
5 days
4 wk
12 wk
Duration
Responders had sustained improvement in
symptoms
Improvement favored the oxybutynin
group.
Peak serum lidocaine concentration was
well below toxic level. No significant side
effects.
No SS difference between the response to l
-arginine and placebo. Three patients
withdrew because of side effects.
Using an intention to treat approach, there
were no differences between groups
Comments
No difference between pre- and post- Increase in bladder capacity in patients with
trial values in PPS and placebo
anatomically verified PBS/IC
groups
Subjective and objective
Minor side effects
improvement in all parameters in
PPS group
Subjective improvement ⬎25% in
Minor side effects
28% of PPS group vs. 13% placebo
(P ⫽ 0.03). Objective improvement
in 26% in PPS vs. 11% placebo (P
⫽ 0.04)
Improvement in 32 in PPS group vs.
16% placebo (P ⫽ 0.01). Reduced
pain and urgency (P ⫽ 0.04, P ⫽
0.01) in PPS group
3/14 patients responded in
hyperbaric oxygen vs. 0 in control
(P ⫽ 0.52).
SS improvement in all parameters in
both oxybutynin and control
group.
Improvement in 30 vs. 9.6% in
placebo (P ⫽ 0.012). The effect
maintained beyond the end of
treatment.
Improvement in 29 vs. 8% in placebo
(P ⫽ 0.07). Improve of GRA in 48
vs. 24% in placebo (P ⫽ 0.05).
Decrease of pain (P ⫽ 0.04)
SS reduction in overall symptom
score in l -arginine group, but not
in other variables.
Results
Parsons (110)
2008
2000
1999
Year
Lidocaine intravesically
Nickel (53)
Cartledge (74)
l-Arginine
Korting (73)
Treatment Study
Table 2. (Continued)
6
2005
1997
2008
Nickel (59)
PPS intravesical
Bade (113)
Davis (87)
2005
Payne (116)
163
22
18
41
20
380
64
121
No. of
Patients
Single application
Single application
Single application
12 wk
12 wk
32 wk
24 wk
18 wk
Duration
Comments
No improvement in symptom in
treatment group at 12-wk followup
In treatment group SS improvement
in pain, frequency, nocturia and 30
d and only in frequency at 3 mo.
No improvement in placebo
group.
40% of patients in PPS group vs.
20% in placebo (P ⫽ 0.33). SS
increase in capacity in PPS group
(P ⫽ 0.047)
Symptoms score was greater in PPS
oral ⫹ intravesical group vs oral ⫹
placebo group (P ⫽ 0.04)
Pain during instillation in more than 80% of
patients in treatment group
Dose-dependent increase in instillation pain
4 patients in treatment group reported light
warm or burning sensation during
infusion
No important side effects
Response rate was 31% for
Minor adverse events. No benefit provided
hydroxyzine vs. 20% for not
for the majority of patients.
treated (P ⫽ 0.26) and 34% for PPS
vs. 18% for no PPS group (P ⫽
0.064)
Response (based on GRA) 75% for
More adverse effects in CyA group
Cya vs. 19% for PPS (P ⬍ 0.001)
Significant symptom improvement (P Response to treatment was not dose
⬍ 0.001) for all doses
depended
Results
BCG, bacillus Calmette-Guerin, DMSO, dimethyl sulfoxide; PPS, sodium pentosanpolysulfate; GRA, Global Response Assessment; SS, statistically significant; CyA,
cyclosporine.
2005
Chen (115)
2000
2005
Sairanen (70)
Resiniferatoxin intravesical
Lazzeri (114)
2003
Year
Sant (58)
Treatment Study
Table 2. (Continued)
7
2005
Quercetin
Theoharides (120)
37
10
48 wk
4 wk
24 wk
12 wk
24 wk
12 wk
2 wk
72 wk
48 wk
24 wk
No significant side effects. Patients with
refractory PBS/IC.
Hyaluronic acid was given intravesically
along with chondroitine sulfate
Patients with less favorable PPS
response had the greatest benefit. No
placebo control.
Patients had Hunner’s ulcers and failed
conventional treatments. 64% of
patients continued treatment at 16 mo.
Oral therapy. Patients had already
failed conventional treatments
Patients had classic PBS/IC features
and positive potassium test
Patients had already failed conventional
treatments
Patients had already failed conventional
treatments
Short-term improvement with pain
recurrence in all pts at 12 mo. Repeat
injections may be required.
Comments
Cystoprotek was formulated with
chondroitine and hyaluronate
Bladder capacity and symptoms significantly improved No major side effects
GAS and symptom index improved (P ⬍ 0.0001)
GAS and symptom index improved (P ⬍ 0.05)
Pain, frequency, and nocturia significantly improved at No side effects reported. Patients had
3 mo
detrusor mastocytosis.
Improvement in pain (P ⫽ 0.047), without signigicant
change in voiding pattern. 44% of patients
responded.
Improvement in number of voiding and voiding
volume
10 responders at 3 mo and 9 responders at 6 mo in PPS
⫹ heparin SC vs. 0 in control (PPS alone)
22% reduction in O’Leary index (P ⬍ 0.02), 69%
improvement in pain control (P ⬍ 0.001)
GAS, O’Leary symptom index significantly improved
(P ⬍ 0.05)
46% of patients had good, 15% fair, 31% partial
response, and 1 did not respond
GAS, Global Assessment Scale; PPS, sodium pentosanpolysulfate; SS, statistically significant; CyA, cyclosporine.
14
2001
Montelukast
Bouchelouche (123)
9
2000
1999
Methotrexate
Moran (80)
23
22
2008
Hyaluronic acid
Porru (97)
58
2001
2005
Heparin
Van Ophoven (122)
14
18
Results
Single
Improvement in bladder capacity and pain score in
therapy
only 2 patients
Single
Frequency, bladder capacity improved at 1 and 3 mo
therapy
(P ⬍ 0.05)
Single
Symptoms improved in 87% of patients at 3 mo, in 27%
therapy
at 5 mo, and none at 12 mo. Short-term improvement
(3 mo) with pain recurrence in all patients at 12 mo
Duration
Katske (124)
Sulplatast tosilate
Ueda (125)
2005
Corticosteroids
Soucy (77)
2002
37
Chondroitin sulphate
Theoharides (120)
2005
Steinhoff (121)
15
2008
Giannantoni (119)
12
10
No. of
patients
2006
2005
Year
Giannantoni (118)
Botulinum A
Kuo (117)
Treatment Study
Table 3. Various PBS/IC treatments for which there are only open label studies available.
8
effective with significant improvement of symptoms (65). However, there were no details regarding the use of active or inactive placebo. The median dose used was 75 mg/d (range, 15 to
150 mg/d). In addition, long-term follow-up (19.0 ⫾ 12.5 mo) of
patients treated with amitriptyline was correlated with a 64%
response rate (66). It is noteworthy that there was a significant
withdrawal of patients in this study because of nonresponse
and anti-cholinergic side effects. Therefore, patients should
start on the lowest possible dose (10 mg daily) and titrate up to
the effective dose (66,67). Results (unpublished) presented by
the Interstitial Cystitis Collaborative Research Network (ICCRN) at the 2009 American Urological Association meeting
showed lack of efficacy of amitriptyline.
Cyclosporine is a calcineurin inhibitor that may act in
PBS/IC through inhibition of activation of T cells or mast cell
activation. Data are limited, but it gave promising results in
small open-label studies (68,69) and in a recent RCT, where
patients treated with cyclosporine reported a higher treatment
response in comparison with PPS treatment after 6 mo (70). In
addition, the response correlated with a decrease in urinary
epidermal growth factor concentration, whereas patients in the
cyclosporine group had a tendency toward lower urinary IL-6
levels (71). However, symptoms may return after treatment
cessation, and side effects are more common in the cyclosporine
group.
Oral cimetidine was found to be very effective, with significant symptom improvement in the only RCT available (72).
However, there was no apparent histologic change in the bladder mucosa after treatment, and the mechanism of symptom
relief is rather undefined. l-Arginine is a substrate for NO
synthase, and it was used in PBS/IC based on data that NO
synthase activity is decreased in the urine of PBS/IC patients.
Two recent RCTs reported limited efficacy with no or marginal
improvement in the treatment group (Table 2) (73,74). Although some patients reported that use of antibiotics might
decrease their symptoms, a recent RCT failed to show benefit
from oral administration of antibiotics for 18 wk (75).
There are numerous other oral treatments, which have been
used in PBS/IC, particularly in refractory cases, but data are
scarce and based on small open label studies, sometimes of
ambiguous design (Table 3); RCTs are urgently needed. Steroids were used in PBS/IC based on the hypothesis that ulcers
signify underlying bladder inflammation (57,76); nevertheless,
there is the caveat that normal bladders are rarely biopsied, so
there are no well-established cut-points at which bladder inflammation is defined as abnormal. Data that steroids are effective in classic PBS/IC are extremely limited, and further
well-designed studies are needed before steroid use can be
widely recommended. Soucy and Gregoire (77) reported symptom improvement after corticosteroid use in 14 patients with
refractory PBS/IC who failed conservative treatment.
Montelukast, a leukotriene receptor antagonist, which is used
in asthma treatment, was also reported to reduce symptoms in
10 patients with detrusor mastocytosis (78). Nonsteroidal antiinflammatory drugs have been used in a small open label study
with 37 patients who reported symptom improvement (79);
however, the anti-depressant agent doxepin was given simul-
9
taneously making difficult the evaluation of efficacy of each
medication and in addition, symptoms recurred after the discontinuation of the treatment. Methotrexate was used in a
study of 9 patients with refractory PBS/IC, with improvement
in one half of them in pain control but not urinary frequency
(80). The significant side effects of these medications should
always be considered.
Intravesical Therapies
Intravesical treatments for PBS/IC were recently analyzed in
a Cochrane review (52): only bacillus Calmette-Guerin (BCG)
and oxybutin seemed to be relatively well tolerated and gave
the most promising results. However, it was repeatedly noted
by the authors that the available evidence is extremely limited.
Dimethyl sulfoxide (DMSO) is the only intravesical medication approved by the FDA. The mechanism of action includes
inhibition of mast cell activation with analgesic and inflammatory effects. Two rather small RCTs support its beneficial effect
(81,82). However, the side effects of DMSO (garlic-like smell,
taste) makes it almost impossible to perform a real placebocontrolled RCT. In addition, in these two early studies, DMSO
was administered every 2 wk, whereas nowadays in common
practice, DMSO is administered once weekly. Finally, in the
crossover study by Peeker et al. (82), where DMSO could follow
BCG treatment and vice versa, there was no clear washout
period between treatments, making it difficult to determine
which treatment was actually beneficial.
Intravesical administration of BCG was initially shown to be
beneficial in PBS/IC through an unknown immunologic mechanism; however, an RCT in 248 PBS/IC patients showed that
BCG treatment was only slightly superior to placebo (83). In
addition, in two other RCTs, the group receiving intravesical
BCG had no or marginal improvement (82,84). Oxybutynin,
which has an anti-cholinergic effect reducing bladder spasm,
was shown to significantly increase bladder capacity and was
correlated with reduced frequency and improved quality of life
(85). In this RCT, 36 patients in both groups with PBS/IC had
significant improvement favoring the oxybutynin group.
Because PBS/IC is associated with chronic pain produced by
sensitized local bladder afferent nerves, a rational approach
would be to install local anesthetic. Toward this direction,
intravesical lidocaine have been used for many years but offered only superficial bladder anesthesia, because lidocaine
cannot be converted to a lipid-soluble base form in the acidic
bladder environment. However, when combined with bicarbonate, its absorption increases, giving promising results (86).
A recent well-designed RCT showed that intravesical alkalinized lidocaine is effective in a large proportion of PBS/IC
patients not only for short-term relief, but it may also contribute
to long-term downregulation of bladder sensory nerves (53). In
addition, duration of treatment may enhance the clinical benefits without significant adverse effects or rebound effects such
those associated with narcotics’ administration.
PPS has also been used intravesically based on the hypothesis that it replenishes the protective bladder lining composed
primarily by glycosaminoglycans layer; additionally, only 6%
10
of PPS is excreted in urine when given orally (61). A recent RCT
showed that combined therapy of intravesical and oral PPS led
to two-fold reduction in the severity of PBS/IC symptoms
compared with oral therapy alone (87).
Despite initial promising results, the effectiveness of resinifera toxin and botulinum toxin type A (88) in the treatment of
PBS/IC remains unknown. We recently showed that the results
from available clinical trials including three RCTs (Table 2)
regarding the efficacy of resinifera toxin are rather inconclusive
(89). Consistent with this, the aforementioned Cochrane review
found no evidence of effect of resinifera toxin for most outcomes; in addition, it reduced patient compliance by causing
pain (52).
Several other intravesical treatments have been tried in
PBS/IC patients, but data are limited, coming from small uncontrolled open-label studies. Heparin has been widely used
intravesically for PBS/IC in combination with lidocaine and
bicarbonate (86) as a substitute for bladder layer or as a inhibitor of inflammation (20). However, when used as monotherapy, it was not shown to provide any relief. Hydrodistention is mainly used for diagnosis, and it remains rather
controversial whether it can also offer short-term relief (55);
there is only a small open-label study that showed that adjuvant hydrodistention under epidural anesthesia can be effective
in almost 70% of patients (90). Similarly, the use of intravesical
hyaluronic acid in PBS/IC may be effective as shown in several
open-label studies (91–96), but in a recent review, we concluded
that it cannot be recommended because of the limited available
data (97). A new open-label study, however, supports that the
administration of intravesical hyaluronic acid plus chondroitin
sulfate may represent a safe and efficacious method of treatment in PBS/IC (98) (Table 3).
nique used and the technical improvements of the newer devices, complications rate of this technique is expected to
decrease (101).
Reconstructive surgery for PBS/IC patients gave disappointing results in the past (102). In addition, a recent study (103)
showed that medical therapy was perceived to be superior to
invasive therapy in PBS/IC. Moreover, surgery was correlated
with failure to resolve symptoms and several complications in
patients with nonulcer PBS/IC. However, a good outcome was
recently reported (104,105) in two studies of patients with classic PBS/IC who underwent reconstructive surgery after failure
of various treatments including transurethral resections and
intravesical installations. Nevertheless, reconstructive surgery
should be reserved only for patients who fail conservative
treatment and those with classic PBS/IC; these patients are
likely to benefit most.
PBS/IC is chronic multifactorial disease of unclear etiology
significantly affecting quality of life and increasing medical
costs; average yearly cost per PBS/ICC patient is ⬃$4000 more
than that for age-matched controls (106). Close follow-up of the
patients is essential, because prolonged administration of medications may be needed before the alleviation of symptoms.
Although lack of numerous RCTs regarding its management is
obvious, we propose a treatment algorithm (Figure 2), based on
the best available evidence and giving priority to the less toxic
therapies, reserving the more invasive treatments and those
with significant adverse effects for the refractory cases.
Evaluation of treatment efficacy in PBS/IC is complicated
Oral therapies
Hydroxyzine, amitriptyline, PPS
Supportive therapies (psychosocial, behavioral, physical) ± analgesia
Other Treatments
In cases of PBS/IC, which are refractory to oral and intravesical treatment, therapeutic options include transurethral resection of ulcers, reconstructive surgery, and neuromodulation.
The cost-benefit ratio should always be considered before one
of these invasive treatments is recommended.
Transurethral resection of ulcers in PBS/IC patients led to
satisfactory response in 90% of patients with classic PBS/IC
(99); the mechanism might involve the removal of the intramural nerve endings. However, this study was not randomized,
and patients underwent hydrodistention before transurethral
resection of ulcers. In addition, the patients of the study (classic
PBS/IC) belong to a subgroup of PBS/IC patients that represent only 5% of PBS/IC patients.
Based on the hypothesis that PBS/IC symptoms may arise
from a chronic simulation and pathologic upregulation of the
pelvic nerves, sacral neuromodulation using an implantable
neuroprosthetic device (which was shown to be effective in
treating urgency and frequency) was reported to decrease narcotic requirements in refractory PBS/IC (100). Although results
are rather promising, drawbacks of this technique include high
cost, pain at the neurostimulator site, need for surgical revisions, and risk of infection. Because of the less invasive tech-
No response
Consider
Intravesical therapies
Hydrodistention, alkalized lidocaine, sodium
hyaluronate, chondroitine sulfate, BCG,
oxybutin, DMSO, PPS
Hyperbaric oxygen
No response
Consider
Other therapies
Immunosuppression
Electric neuromodulation
No response
Consider
Reconstructive surgery
Figure 2. Treatment algorithm for interstitial cystitis. BCG, bacillus Calmette-Guerin; PPS, pentosan polysulfate sodium;
DMSO, dimethyl sulfoxide.
because of the short duration of trials, the heterogeneity of
disease, and the lack of evidence for its natural history. The
NIDDK-sponsored trial (58) showed the feasibility of conducting a multicenter RCT in PBS/IC using uniform procedures
and outcomes. It is crucial not only to recruit patients following
specific inclusion criteria, but also to define objective outcome
measures and to continue follow-up for a long period of time
after intervention. The latter is essential in a disease with flares
and remissions, which would otherwise make it almost impossible to attribute improvement to the intervention and not to
disease fluctuation itself. In addition, there should be a consensus regarding objective standardized outcome measures (working or activity hours, physical or sexual activity, etc.); this is
particularly significant to ensure that improvement is actually
accomplished and that it is not the result of frequent subjective
changes observed in patients with chronic disease. Intervention
should follow the same protocol to allow a more accurate
comparison between trials. Developing evidence-based therapies by conducting appropriately designed RCTs is essential for
advancing to safe and effective interventions in patients with
this chronic and debilitating disease.
Disclosures
None.
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Interstitial Cystitis: An Unsolved Enigma Mini-Review Dimitrios-Anestis Moutzouris* and Matthew E. Falagas

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