International Journal of Urology (2016) 23, 542--549 doi: 10.1111/iju.

13118

Guideline

Clinical guidelines for interstitial cystitis and hypersensitive bladder

updated in 2015
Yukio Homma,1 Tomohiro Ueda,2 Hikaru Tomoe,3 Alex TL Lin,4 Hann-Chorng Kuo,5 Ming-Huei Lee,6
Seung-June Oh,7 Joon Chul Kim8 and Kyu-Sung Lee9
1
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, 2Department of Urology, Ueda Clinic,
Kyoto, 3Department of Urology, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan, 4Department of Urology,
National Yang Ming University and Taipei Veterans General Hospital, Taipei, 5Department of Urology, Buddhist Tzu Chi General
Hospital and School of Medicine, Tzu Chi University, Hualien, 6Department of Urology, Feng-Yuan Hospital, Taichung, Taiwan,
7
Department of Urology, Seoul National University, Seoul, 8Department of Urology, The Catholic University of Korea, Seoul, and
9
Department of Urology, Sung Kyun Kwan University School of Medicine, Seoul, Korea

Abbreviations & Acronyms
APF = antiproliferative
factor
BCG = bacillus Calmette–
Gu
erin
BPS = bladder pain
syndrome
DMSO = dimethyl sulfoxide
HSB = hypersensitive
bladder
IC = interstitial cystitis
MBAD = mucosal bleeding
after distension
NGF = nerve growth factor
PBS = painful bladder
syndrome
QOL = quality of life
TENS = transcutaneous
electric nerve stimulation
Abstract: Clinical guidelines for interstitial cystitis and hypersensitive bladder have
been updated as of 2015. The guidelines define interstitial cystitis by the presence of
hypersensitive bladder symptoms (discomfort, pressure or pain in the bladder usually
associated with urinary frequency and nocturia) and bladder pathology, after excluding
other diseases explaining symptoms. Interstitial cystitis is further classified by bladder
pathology; either Hunner type interstitial cystitis with Hunner lesions or non-Hunner type
interstitial cystitis with mucosal bleeding after distension in the absence of Hunner
lesions. Hypersensitive bladder refers to a condition, where hypersensitive bladder
symptoms are present, but bladder pathology or other explainable diseases are
unproven. Interstitial cystitis and hypersensitive bladder severely affect patients’ quality
of life as a result of disabling symptoms and/or comorbidities. Reported prevalence
suggestive of these disorders varies greatly from 0.01% to >6%. Pathophysiology would
be an interaction of multiple factors including urothelial dysfunction, inflammation, neural
hyperactivity, exogenous substances and extrabladder disorders. Definite diagnosis of
interstitial cystitis and hypersensitive bladder requires cystoscopy with or without
hydrodistension. Most of the therapeutic options lack a high level of evidence, leaving a
few as recommended therapeutic options.
Key words: guidelines, Hunner lesions, hypersensitive bladder, interstitial cystitis.

Correspondence: Yukio
Homma M.D., Department of
Urology, Graduate School of
Medicine, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-
ku, Tokyo 113-8655, Japan.
Email: homma-uro@umin.ac.jp
Received 7 March 2016;
accepted 5 April 2016.
Online publication 24 May 2016
Introduction
Clinical guidelines are to be revised regularly by incorporating scientific progress. We have
summarized the advances in the basic science and clinical management of interstitial cystitis
during these 6 years since the last publication. The readers are kindly advised to look at the
previous guidelines; most of the previous descriptions and references are not repeated for the
sake of conciseness.1
Methods
The previous guidelines for interstitial cystitis and hypersensitive bladder syndrome were
updated using materials identified by the PubMed database published from 2008 to the end of
2015 including e-publications.1 Guidelines issued by the American Urological Association or
European Society for the Study of IC were also counselled.2–4

Definition
There is no widely accepted definition of IC and related conditions. A lack of definition has
incurred confusion by creating many terms: PBS, BPS, IC/PBS (PBS/IC) and IC/BPS (BPS/IC)
are examples.2–4 In reality, however, these terms are used interchangeably without distinction.
Another source of confusion is “pain” in PBS and BPS; a significant proportion of IC patients
do not complain of pain. The symptoms could be rather characterized as “hypersensitive,” as

542 © 2016 The Japanese Urological Association


urothelium is a sophisticated sensory tissue,5 and sensory
hyperactivity is implicated in bladder disorders including IC.6,7
Thus, in the current guidelines, we used the previous definition
with slight modification (Table 1). IC is defined by hypersensi-
tive bladder symptoms and bladder pathology after excluding
other diseases explaining symptoms. Bladder pathology is
either a Hunner lesion or MBAD. The condition with hyper-
sensitive bladder symptoms, but no proven bladder pathology
or other explainable diseases, is designated as HSB.8
Pathophysiology
Pathophysiology of IC and HSB would be a complex of mul-
tiple factors.
Urothelial dysfunction
Alterations of urothelial differentiation and homeostasis are
shown by denudation of the epithelium,9 low expression of
interleukin-8,10 increased levels of apoptosis with decreased
proliferation,11,12 or abnormal expression of APF, uroplakin,
chondroitin sulfate and tight junctional proteins. Dysregulated
urothelium can result in increased permeability, generating
hypersensitive bladder symptoms.13 In turn, glycosaminogly-
can substitutes or APF antagonists normalize permeability.14,15
Hypersensitive symptoms in recurrent urinary tract infection
might be explained by increased urothelial cell apoptosis.16
Inflammation
IC patients have high urinary concentrations of immunoglobu-
lin and inflammatory markers,17–20 or high serum levels of C-
reactive protein, NGF and pro-inflammatory cytokines.21–24
Bladders with Hunner type IC show diffuse and intense inflam-
mation9 and overexpression of pro-inflammatory genes.6,7,25–27
Light-chain restriction in infiltrated plasma cells suggests
involvement of specific immunological reactions.9 Bladder
inflammation is likely to induce afferent nerve overactivity.28
Neural hyperactivity
IC bladders show upregulation of TRPV1,7,29 or increased
release of NGF, ATP and prostaglandins.30 Overexpression
Table 1 Definition of IC and HSB
Criteria
IC 1. Hypersensitive bladder symptoms†
2. Bladder pathology‡
3. No other diseases explaining symptoms
Subtype of IC Hunner type IC: IC with Hunner lesions
Non-Hunner type IC: IC with MBAD in the absence of
Hunner lesions
HSB 1. Hypersensitive bladder symptoms
2. No proven bladder pathology or other
explainable diseases
†Discomfort, pressure or pain in the bladder usually associated with
urinary frequency and nocturia. ‡Hunner lesions or MBAD.
© 2016 The Japanese Urological Association
Clinical guidelines for IC and HSB
of NGF leads to neuronal hyperinnervation, nervous hyperac-
tivity and bladder dysfunction.31 Urinary NGF levels are clo-
sely related to pain score and therapeutic responses.32
Systemic or central neural hyperactivity is indicated by
increased sympathetic nerve activity,33–36 segmental hyperal-
gesia with spinal sensitization,37 or increased mental stress
and multiple sensitivities38 in IC patients.
Impaired microcirculation
IC bladders show increased expression of angiogenic growth
factors and apoptosis of endothelial cells. Increased and dys-
regulated angiogenesis is implicated with mucosal bleeding
after distension.39,40 Intravesical onabotulinumtoxin A injec-
tions downregulate vascular endothelial growth factors.41
Exogenous substances and infection
Consumption of specific diet triggers symptom worsening.42
Chronic ketamine abuse causes bladder inflammation associ-
ated with immunological hypersensitivity.43 Urine alkalization
by citrate improved HSB symptoms.44
Association of IC and infection of a microorganism or
virus has not been confirmed, although women with recurrent
urinary tract infection have increased urothelial cell apoptosis,
increased mast cell count and lower E-cadherin, which could
cause the hypersensitivity symptoms in these women.16
Extrabladder disorders
IC patients have a higher risk for irritable bowel syndrome,
fibromyalgia, general fatigue, functional somatic syndrome,
comorbid neurological diseases, rheumatological diseases and
mental illnesses.33,45–49 Neuronal cross-talk with pelvic
organs might exaggerate bladder symptoms; patients have a
higher risk for prior hysterectomy;46 pelvic myofascial pain is
implicated with therapeutic response.50
Epidemiology
The known prevalence of IC or conditions suggestive of IC
ranged from 0.01% to 2.3%, with an approximately fivefold
female dominance.1 The RAND Interstitial Cystitis Epidemiol-
ogy study found approximately 2.70–6.53% of women met the
high specificity and high sensitivity IC symptom criteria.51 In
Japan, 1.0% of the general population experienced bladder pain
every day, and the actual number of IC and HSB patients under
medical care was estimated as approximately 4500 (0.004%).52
In Korea, a population-based cross-sectional survey showed
the prevalence of IC as 0.26% in women.53 The prevalence in
Taiwan was 22 per 100 000 people (0.022%).54 IC patients
have a higher risk for prior non-bladder surgery,55 or non-blad-
der pain and hypersensitive syndromes.33,45–49
Diagnosis
The diagnosis of IC is made by the presence of symptoms
and bladder pathology (Table 1). Symptomatic patients with-
out bladder pathology are diagnosed as HSB.8
543
Y HOMMA ET AL.
Symptoms and QOL
Common symptoms of IC and HSB are discomfort, pressure
or pain in the bladder usually associated with urinary fre-
quency and nocturia. These symptoms are collectively called
HSB symptoms. Bladder pain would be the most typical
symptom. However, a substantial portion of patients do not
complain of pain. Symptoms are susceptible to dietary, envi-
ronmental and mental stress, with variable remissions and
exacerbations.56 Many symptom assessment tools are avail-
able, although a single specific questionnaire cannot offer
complete assessment.57 The QOL is negatively affected by
HSB symptoms; patients had lower economic status, painful
sex and sleep disorders.58 Bladder pain, depressive symp-
toms, physical disability, comorbidities and less work partici-
pation were related to each other.59,60
Clinical examinations
Urinalysis usually showed no abnormality. Urinary diaries
showed increased urinary frequency and constant small
voided volumes all day.61
Cystoscopy
Cystoscopy is required for the diagnosis of Hunner type IC.
A Hunner lesion is recognized as a reddish mucosal lesion
lacking in the normal capillary structure associated with con-
verging vessels, covering fibrin clots or scars in the vicinity
(Fig. 1). A highly variable proportion of patients with Hun-
ner lesions among hospitals suggest inconsistent diagnostic
criteria for the lesions.52 It is crucially important to watch
the bladder mucosa from the early phase of filling, as Hun-
ner lesions might be obscured soon after bladder distension.
The lesions are more readily recognized by narrow-band
imaging cystoscopy.
Hydrodistension
Hydrodistension is not simple overdistension of the bladder
by hydrostatic pressure, but inclusive of careful observation
of the bladder mucosa during distension and emptying. It is
preferably carried out under general or spinal anesthesia for
(a) (b)
544
thorough observation, which should be recorded in a stan-
dardized way.1 Hunner lesions sometimes rupture during dis-
tension, and waterfall bleeding occurs on deflation. A bladder
that appears normal before distension might undergo MBAD
during emptying (Fig. 2). MBAD and glomerulations are not
identical; MBAD donates mucosal bleeding seen during the
first emptying, whereas glomerulations describe spotty sub-
mucosal hemorrhages found at the second filling.62 A recent
review article has provided no convincing evidence that
glomerulations should be included in the diagnosis or pheno-
typing of IC.62 However, MBAD is an obvious abnormal
endoscopic finding, and would represent some bladder
pathology.
Bladder biopsy
Bladder biopsy might not be essential for diagnosis. How-
ever, Hunner type IC shows epithelial denudation and dense
inflammatory infiltrates in the bladder, which are totally dif-
ferent from non-Hunner type IC or HSB.9
Biomarkers
Numerous diagnostic biomarkers are explored including APF,
urinary18,19 or serum24 NGF, and urinary or serum pro-
inflammatory cytokines or chemokines.22 An intratissue
increase in chemokines or receptors related to pro-nociceptive
inflammatory reactions has been reported.7 However, there
are no universally accepted biomarkers.63
Other diseases to be excluded
Many diseases can cause HSB symptoms thus to be
excluded. The examples are bladder diseases (overactive
bladder, neurogenic bladder, bladder cancer, bladder calcu-
lus, radiation cystitis, chemical cystitis, ketamine-related cys-
titis), prostate and urethral diseases (benign prostatic
hyperplasia, prostate cancer, urethral cancer, urethral divertic-
ulum, urethral stricture), genitourinary infections (bacterial
cystitis, urethritis, prostatitis), gynecological diseases (gyne-
cological malignancies, endometriosis, uterine myoma,
vaginitis, climacteric disturbance) or other conditions (poly-
uria, urinary stones).
Fig. 1 Hunner lesion. (a) A Hunner lesion is a
reddish mucosal lesion lacking in the normal
capillary structure. It is often associated with
converging vessels, covering fibrin clots and scars
in the vicinity. (b) The lesions are more readily
recognized by narrow-band imaging cystoscopy.
© 2016 The Japanese Urological Association

(a)
Fig. 2 MBAD. The (a) apparently normal bladder
mucosa shows (b) intravesical rainy bleeding
during bladder emptying after distension.
Recommended tests
Diagnostic tests were classified according to recommendation
level (Table 2).
Treatment
The grade of recommendation as previously determined is
shown in Table 3.1 Therapies with no major progress during
these 7 years were not mentioned in the text.
Conservative treatment
Dietary modification by avoiding acidic foods, high-potas-
sium foods, coffee, tea, soda, spicy foods, artificial sweetener
and alcohol is beneficial.64 Behavioral therapy with controlled
fluid intake and bladder training improve frequency–ur-
gency.65 A randomized study showed the efficacy of physical
therapy with myofascial therapy in improving pelvic pain.66
The guided imagery technique also helps to reduce pelvic
floor tonicity and pain. Psychological support from a spouse
or patient support groups is an indispensable component of
IC therapy.67 Management using the biopsychosocial model
was effective in recovering QOL impairment.67,68
Medical treatment
Pentosan polysulfate
Pentosan polysulfate can improve symptoms by repairing the
damaged glycosaminoglycan layer of the urothelium. How-
ever, the results of placebo-controlled double blind studies
are conflicting. A recent double-blind, randomized, placebo
study showed no statistically significant improvement com-
pared with a placebo.69
Table 2 Clinical tests for diagnosis
Mandatory Clinical history, physical examinations, urinalysis
Recommended Urine culture, urine cytology, symptom scores,
QOL scores, frequency–volume chart,
residual urine measurement, prostate-specific antigen,
cystoscopy with or without hydrodistension
Optional Urodynamic study, pelvic imaging tests, bladder biopsy
© 2016 The Japanese Urological Association
Clinical guidelines for IC and HSB
(b)
Amitriptyline
Amitriptyline is expected to inhibit mast cell activity and to
modify pain transmission in the central nervous system.
Uncontrolled or double-blind studies showed modest efficacy.
However, a recent randomized double-blind study showed no
statistically significant efficacy over a placebo.70 The
response rate was significantly higher (66%) than the placebo
(47%) in a subgroup who achieved a drug dose of at least
50 mg.
Cyclosporine A
The efficacy of cyclosporine was shown in open trials and a
randomized study. A retrospective review showed a high suc-
cess rate (68%) for patients with Hunner lesions compared
with those without (30%).71 Close monitoring is required, as
adverse events can be serious.
Steroid
Oral steroid might be indicated for Hunner type IC resistant
to other treatments or IC accompanied by autoimmune dis-
eases, such as systemic lupus erythematosus and Sj€ ogren’s
syndrome.72 Adverse events might be associated in long-term
treatment.
Citrate
Alkalization of urine by citrate improved HSB symptoms
and QOL impairment with an increase in single voided
volume.44
Intravesical instillation or bladder wall
injection
DMSO
Randomized and non-randomized studies showed some effi-
cacy.73
Heparin
Previous and recent open studies showed efficacy of heparin
or heparin combined with alkalized lidocaine.74,75
Hyaluronic acid
Many reports showed a long-lasting moderate efficacy with
no significant toxicity.76
545
Y HOMMA ET AL.

Table 3 Treatments for IC and HDB

Grade of recommendation Suggested doses†

Treatment (level of evidence) or indication
Conservative treatment B or C (2–4)
Medical treatment Pentosan polysulfate C/B (2, 2)‡ 300 mg/day
Amitriptyline B/C (2, 2) 10–75 mg/day
Hydroxyzine§ C (4) 25–75 mg/day
Suplatast tosilate§ C (4) 300–600 mg/day
Cyclosporine A C (2) 3 mg/kgBW/day
Steroid (prednisolone) C (4) 5–25 mg/day
Cimetidine§ C (2) 600 mg/day
Antibacterial agent§ D (2)
L-arginine§ D (4, 2)
Citrate C (4) 853 mg/day
Intravesical instillation or DMSO B (2) 50 mL of 50% solution
bladder wall injection Heparin C (4) 10 000 units
Hyaluronic acid C (4) 40 mg
Chondroitin sulfate C (4, 2) 0.2–2%
Pentosan polysulfate§ C (2) 300 mg
Oxybutynin§ C (2) 0.01%
Lidocaine C (4) 4%
Resiniferatoxin§ C (4, 2) 10–100 nmol/L
Botulinum toxin B (2) 100–200 IU
Steroid C (4) 40 mg/mL 10 mL
BCG§ D (2, 2)
Hydrodistension B/C (4)
Other treatments TENS§ C (3)
Neuromodulation B (2)
Acupuncture C (3, 3)
Hyperbaric oxygen C (4, 2)
Fulguration B (3) Hunner type IC only
Cystectomy or augmentation C (4) Last resort

†Only for the treatments with grade of recommendation B and C. ‡Level of evidence for efficacy, level of evidence for non-efficacy. §No major progress during
these 6 years.

Chondroitin sulfate Hydrodistension

Single or combined instillation with hyaluronic acid showed
symptom improvement. However, it was negated in a ran-
domized double-blind controlled study.77
Lidocaine
Lidocaine can relieve pain by blocking sensory nerves for a
short time. Alkalization of lidocaine is believed to promote
absorption.74
Botulinum toxin
Single-arm or randomized studies showed symptom relief by
botulinum toxin injection, single or repeated, into the bladder
wall.78,79 The average duration of effect was approximately
6 months, and repeated injections seem to be necessary. It is
uncertain whether the presence of Hunner lesions affects the
efficacy of injection.80,81
Steroid
Submucosal injections of a corticosteroid in and around Hun-
ner lesions offered significant symptomatic improvement.82
Most reports showed an approximately 50% efficacy rate and
a few-month efficacy persistence. The putative mechanism
for efficacy includes degeneration of afferent nerves, anti-
inflammatory effect or reduction of nerve growth factor.32 A
study identified concomitant lumbar spinal stenosis and irrita-
ble bowel syndrome as predictors for poor outcomes.83 Sug-
gested procedures for hydrodistension were described
previously.1
Other treatments
Electrostimulation
The efficacy of permanent sacral nerve neuromodulation was
shown in many studies, and confirmed in a long-term obser-
vation.84,85 Intermittent posterior tibial nerve stimulation or
pudendal nerve stimulation also showed efficacy.
Acupuncture
A large placebo effect, and contradictory results with limited
and temporary efficacy were reported.86

546 © 2016 The Japanese Urological Association

 Clinical guidelines for IC and HSB

Hypersensitive bladder symptoms

Basic evaluation

Hypersensitive bladder (HSB)

Conservative or medical treatment Other diseases

Not improved Cystoscopy (+Hydrodistension)

Treatment
IC (Hunner or non-Hunner) or non-IC HSB

Hydrodistension, fulguration of Hunner lesion

Not improved

Repeated or combined treatment with instillation, injection, and electrostimulation,

or cystectomy

Fig. 3 Clinical algorithm for hypersensitive bladder symptoms. This algorithm is for patients presenting with HSB symptoms (discomfort, pressure or pain in the
bladder usually associated with urinary frequency and nocturia). The basic evaluation consists of the mandatory evaluation (history taking, physical findings and uri-
nalysis), and recommended or optional tests (see Table 2). When other diseases are identified, appropriate treatments should be initiated. When IC or HSB is likely,
cystoscopy with or without hydrodistension is recommended to make a definite diagnosis. Alternatively, conservative or medical treatment can be empirically initi-
ated, with cystoscopy carried out when the therapy fails. Hydrodistension is preferentially carried out under spinal or general anesthesia to confirm mucosal bleed-
ing after distension. If Hunner lesions are found on cystoscopy, fulguration of lesions is indicated. In any case, conservative or medical treatment should be
considered concurrently. When sufficient improvement cannot be achieved, consider re-evaluation, repeated treatment or combined treatments with bladder instil-
lation, bladder injection and electrostimulation. Cystectomy is the last resort.

Hyperbaric oxygen therapy Assessment of therapeutic

The efficacy of hyperbaric oxygen was not statistically sig-
nificant in a randomized double-blind trial. However, it
seems to be beneficial in some patients, such as those
with Hunner type IC87 or those after DMSO instillation
therapy.88
Transurethral fulguration
Many studies reported the efficacy of transurethral electro- or
laser fulguration of the Hunner lesions. Recent studies con-
firmed the efficacy, and found pain relief persisted for a few
months to 2 years post-treatment.83,89–91
Cystectomy, augmentation and urinary diversion
Partial or complete cystectomy and bladder augmentation
with or without urinary diversion would be the last resort for
intractable cases, who are resistant to the aforementioned
therapies and still highly symptomatic. Supratrigonal cystec-
tomy with subsequent bladder augmentation using a bowel
segment is the most common continence-preserving tech-
nique.92 Subtrigonal cystectomy with ureteral reimplantation
or total cystectomy with urinary diversion is an alternative
option. Pelvic pain is usually relieved, but occasionally per-
sists after augmentation and cystectomy.92 Intermittent
catheterization might be required after neobladder formation.
Patients undergoing cystoplasty need a long-term follow up
for symptom recurrence or possible morbidities including
hydronephrosis and adenocarcinoma in the intestinal portion.
effectiveness
Clinical studies for IC and HSB require special consideration
for the study design, inclusion criteria and outcome measures,
as described previously.1 Outcomes of medical treatment
might not be affected by cystoscopic findings.93
Clinical algorithm
The algorism is constructed for the proper management of
patients presenting HSB symptoms (Fig. 3).
Conflict of interest
None declared.
References
1 Homma Y, Ueda T, Tomoe H et al. Clinical guidelines for interstitial
cystitis and hypersensitive bladder syndrome. Int. J. Urol. 2009; 16:
597–615.
2 van de Merwe JP, Nordling J, Bouchelouche P et al. Diagnostic criteria, clas-
sification, and nomenclature for painful bladder syndrome/interstitial cystitis:
an ESSIC proposal. Eur. Urol. 2008; 53: 60–7.
3 Hanno PM, Burks DA, Clemens JQ et al. AUA guideline for the diagnosis
and treatment of interstitial cystitis/bladder pain syndrome. J. Urol. 2011;
185: 2162–70.
4 Hanno PM, Erickson D, Moldwin R, Faraday MM; American Urological
Association. Diagnosis and treatment of interstitial cystitis/bladder pain syn-
drome: AUA guideline amendment. J. Urol. 2015; 193: 1545–53.

© 2016 The Japanese Urological Association 547

Y HOMMA ET AL.
5 Birder LA, Andersson KE, Kanai AJ, Hanna-Mitchell AT, Fry CH. Urothelial
mucosal signaling and the overactive bladder-ICI-RS 2013. Neurourol. Uro-
dyn. 2014; 33: 597–601.
6 Sanchez-Freire V, Blanchard MG, Burkhard FC, Kessler TM, Kellenberger S,
Monastyrskaya K. Acid-sensing channels in human bladder: expression, func-
tion and alterations during bladder pain syndrome. J. Urol. 2011; 186: 1509–16.
7 Homma Y, Nomiya A, Tagaya M et al. Increased mRNA expression of
genes involved in pronociceptive inflammatory reactions in bladder tissue of
interstitial cystitis. J. Urol. 2013; 190: 1925–31.
8 Homma Y. Hypersensitive bladder: a solution to confused terminology and
ignorance concerning interstitial cystitis. Int. J. Urol. 2014; 21(Suppl 1): 43–7.
9 Maeda D, Akiyama Y, Morikawa T et al. Hunner-type (classic) interstitial
cystitis: a distinct inflammatory disorder characterized by pancystitis, with
frequent expansion of clonal B-cells and epithelial denudation. PLoS ONE
2015; 10: e0143316.
10 Tseng-Rogenski S, Liebert M. Interleukin-8 is essential for normal urothelial
cell survival. Am. J. Physiol. Renal. Physiol. 2009; 297: F816–21.
11 Shie JH, Kuo HC. Higher levels of cell apoptosis and abnormal E-cadherin
expression in the urothelium are associated with inflammation in patients with
interstitial cystitis/painful bladder syndrome. BJU Int. 2011; 108: E136–41.
12 Lee JD, Lee MH. Activation of extrinsic apoptotic pathway from bladder
biopsy in patients with interstitial cystitis/painful bladder syndrome. Urology
2013; 82: e7–11.
13 Parsons CL. The role of a leaky epithelium and potassium in the generation of
bladder symptoms in interstitial cystitis/overactive bladder, urethral syndrome,
prostatitis and gynaecological chronic pelvic pain. BJU Int. 2011; 107: 370–5.
14 Engles CD, Hauser PJ, Abdullah SN, Culkin DJ, Hurst RE. Intravesical chon-
droitin sulfate inhibits recruitment of inflammatory cells in an acute acid dam-
age “leaky bladder” model of cystitis. Urology 2012; 79: e13–7.
15 Keay S, Kaczmarek P, Zhang CO et al. Normalization of proliferation and tight
junction formation in bladder epithelial cells from patients with interstitial cys-
titis/painful bladder syndrome by d-proline and d-pipecolic acid derivatives of
antiproliferative factor. Chem. Biol. Drug Des. 2011; 77: 421–30.
16 Chuang FC, Kuo HC. Increased urothelial cell apoptosis and chronic inflam-
mation are associated with recurrent urinary tract infection in women. PLoS
ONE 2013; 8: e63760.
17 Gamper M, Viereck V, Eberhard J et al. Local immune response in bladder
pain syndrome/interstitial cystitis ESSIC type 3C. Int. Urogynecol. J. 2013;
24: 2049–57.
18 Kim SW, Im YJ, Choi HC, Kang HJ, Kim JY, Kim JH. Urinary nerve
growth factor correlates with the severity of urgency and pain. Int. Urogy-
necol. J. 2014; 25: 1561–7.
19 Jiang YH, Liu HT, Kuo HC. Decrease of urinary nerve growth factor but not
brain-derived neurotrophic factor in patients with interstitial cystitis/bladder
pain syndrome treated with hyaluronic acid. PLoS ONE 2014; 9: e91609.
20 Wilkinson DR, Erickson AD. Urinary and serologic markers for interstitial
cystitis: an update. Curr. Urol. Rep. 2006; 7: 414–22.
21 Logadottir Y, Delbro D, Fall M et al. Cytokine expression in patients with
bladder pain syndrome/interstitial cystitis ESSIC type 3C. J. Urol. 2014; 192:
1564–8.
22 Tyagi P, Killinger K, Tyagi V, Nirmal J, Chancellor M, Peters KM. Urinary
chemokines as noninvasive predictors of ulcerative interstitial cystitis. J. Urol.
2012; 187: 2243–8.
23 Liu HT, Kuo HC. Increased urine and serum nerve growth factor levels in
interstitial cystitis suggest chronic inflammation is involved in the pathogene-
sis of disease. PLoS ONE 2012; 7: e44687.
24 Jiang YH, Peng CH, Liu HT, Kuo HC. Increased pro-inflammatory cytokines,
C-reactive protein and nerve growth factor expressions in serum of patients
with interstitial cystitis/bladder pain syndrome. PLoS ONE 2013; 8: e76779.
25 Colaco M, Koslov DS, Keys T et al. Correlation of gene expression with
bladder capacity in interstitial cystitis/bladder pain syndrome. J. Urol. 2014;
192: 1123–9.
26 Ogawa T, Homma T, Igawa Y et al. CXCR3 binding chemokine and
TNFSF14 over expression in bladder urothelium of patients with ulcerative
interstitial cystitis. J. Urol. 2010; 183: 1206–12.
27 Blalock EM, Korrect GS, Stromberg AJ, Erickson DR. Gene expression anal-
ysis of urine sediment: evaluation for potential noninvasive markers of inter-
stitial cystitis/bladder pain syndrome. J. Urol. 2012; 187: 725–32.
28 Yoshimura N, Oguchi T, Yokoyama H et al. Bladder afferent hyperexcitabil-
ity in bladder pain syndrome/interstitial cystitis. Int. J. Urol. 2014; 21(Suppl
1): 18–25.
548
29 Liu L, Mansfield KJ, Kristiana I, Vaux KJ, Millard RJ, Burcher E. The
molecular basis of urgency: regional difference of vanilloid receptor expres-
sion in the human urinary bladder. Neurourol. Urodyn. 2007; 26: 433–8; dis-
cussion 9; discussion 51–3.
30 Wada N, Ameda K, Furuno T, Okada H, Date I, Kakizaki H. Evaluation of
prostaglandin E2 and E-series prostaglandin receptor in patients with intersti-
tial cystitis. J. Urol. 2015; 193: 1987–93.
31 Schnegelsberg B, Sun TT, Cain G et al. Overexpression of NGF in mouse
urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes
in urinary bladder function. Am. J. Physiol. Regul. Integr. Comp. Physiol.
2010; 298: R534–47.
32 Liu HT, Tyagi P, Chancellor MB, Kuo HC. Urinary nerve growth factor level
is increased in patients with interstitial cystitis/bladder pain syndrome and
decreased in responders to treatment. BJU Int. 2009; 104: 1476–81.
33 Martinez-Martinez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martinez-
Lavin M. Sympathetic nervous system dysfunction in fibromyalgia, chronic
fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review
of case-control studies. J. Clin. Rheumatol. 2014; 20: 146–50.
34 Charrua A, Pinto R, Taylor A et al. Can the adrenergic system be implicated
in the pathophysiology of bladder pain syndrome/interstitial cystitis? A clini-
cal and experimental study. Neurourol. Urodyn. 2015; 34: 489–96.
35 Williams DP, Chelimsky G, McCabe NP et al. Effects of chronic pelvic pain
on heart rate variability in women. J. Urol. 2015; 194: 1289–94.
36 Stav K, Lang E, Fanus Z, Leibovici D. Autonomic response during bladder
hydrodistention in patients with bladder pain syndrome. J. Urol. 2012; 188:
117–21.
37 Lai HH, Gardner V, Ness TJ. Gereau RWt. Segmental hyperalgesia to
mechanical stimulus in interstitial cystitis/bladder pain syndrome: evidence of
central sensitization. J. Urol. 2014; 191: 1294–9.
38 Fuoco MB, Irvine-Bird K, Curtis Nickel J. Multiple sensitivity phenotype in
interstitial cystitis/bladder pain syndrome. Can. Urol. Assoc. J. 2014; 8:
E758–61.
39 Kiuchi H, Tsujimura A, Takao T et al. Increased vascular endothelial growth
factor expression in patients with bladder pain syndrome/interstitial cystitis:
its association with pain severity and glomerulations. BJU Int. 2009; 104:
826–31.
40 Lee JD, Lee MH. Increased expression of hypoxia-inducible factor-1alpha
and vascular endothelial growth factor associated with glomerulation forma-
tion in patients with interstitial cystitis. Urology 2011; 78: e11–5.
41 Peng CH, Jhang JF, Shie JH, Kuo HC. Down regulation of vascular endothe-
lial growth factor is associated with decreased inflammation after intravesical
OnabotulinumtoxinA injections combined with hydrodistention for patients
with interstitial cystitis–clinical results and immunohistochemistry analysis.
Urology 2013; 82: e1–6.
42 Bassaly R, Downes K, Hart S. Dietary consumption triggers in interstitial
cystitis/bladder pain syndrome patients. Female Pelvic Med. Reconstr. Surg.
2011; 17: 36–9.
43 Jhang JF, Hsu YH, Jiang YH, Kuo HC. Elevated serum IgE may be asso-
ciated with development of ketamine cystitis. J. Urol. 2014; 192: 1249–
56.
44 Ueda T, Yoshida T, Tanoue H et al. Urine alkalization improves the prob-
lems of pain and sleep in hypersensitive bladder syndrome. Int. J. Urol.
2014; 21: 512–7.
45 Keller JJ, Chen YK, Lin HC. Comorbidities of bladder pain syndrome/inter-
stitial cystitis: a population-based study. BJU Int. 2012; 110: E903–9.
46 Warren JW, Morozov V, Howard FM et al. Before the onset of interstitial
cystitis/bladder pain syndrome, the presence of multiple non-bladder syn-
dromes is strongly associated with a history of multiple surgeries. J. Psycho-
som. Res. 2014; 76: 75–9.
47 Nickel JC, Tripp DA. International Interstitial Cystitis Study G. Clinical and
psychological parameters associated with pain pattern phenotypes in women
with interstitial cystitis/bladder pain syndrome. J. Urol. 2015; 193: 138–44.
48 Fan YH, Lin AT, Lu SH, Chuang YC, Chen KK. Non-bladder conditions in
female Taiwanese patients with interstitial cystitis/hypersensitive bladder syn-
drome. Int. J. Urol. 2014; 21: 805–9.
49 Clemens JQ, Elliott MN, Suttorp M, Berry SH. Temporal ordering of intersti-
tial cystitis/bladder pain syndrome and non-bladder conditions. Urology
2012; 80: 1227–31.
50 Bassaly R, Tidwell N, Bertolino S, Hoyte L, Downes K, Hart S. Myofascial
pain and pelvic floor dysfunction in patients with interstitial cystitis. Int.
Urogynecol. J. 2011; 22: 413–8.
© 2016 The Japanese Urological Association

51 Berry SH, Elliott MN, Suttorp M et al. Prevalence of symptoms of bladder
pain syndrome/interstitial cystitis among adult females in the United States. J.
Urol. 2011; 186: 540–4.
52 Yamada Y, Nomiya A, Niimi A et al. A survey on clinical practice of inter-
stitial cystitis in Japan. Trans. Androl. Urol. 2015; 4: 486–90.
53 Choe JH, Son H, Song YS, Kim JC, Lee JZ, Lee KS. Prevalence of painful
bladder syndrome/interstitial cystitis-like symptoms in women: a population-
based study in Korea. World J. Urol. 2011; 29: 103–8.
54 Lee MH, Tsai WC. The epidemiologic status of interstitial cystitis and its
associated factors of interstitial cystitis in Taiwan. Int. J. Urol. 2010; 17:
A378.
55 Warren JW, Clauw DJ, Wesselmann U, Howard FM, Gallicchio L, Morozov
V. Functional somatic syndromes as risk factors for hysterectomy in early
bladder pain syndrome/interstitial cystitis. J. Psychosom. Res. 2014; 77:
363–7.
56 Sutcliffe S, Bradley CS, Clemens JQ et al. Urological chronic pelvic pain
syndrome flares and their impact: qualitative analysis in the MAPP network.
Int. Urogynecol. J. 2015; 26: 1047–60.
57 Quaghebeur J, Wyndaele JJ. Comparison of questionnaires used for the eval-
uation of patients with chronic pelvic pain. Neurourol. Urodyn. 2013; 32:
1074–9.
58 Lee MH, Lin TL, Kuo HC, Chen YF. Clinical characteristic picture and
impact of symptoms on quality of life of interstitial cystitis patients in Tai-
wan. Low. Urin. Tract Symptoms 2014; 1: 20–5.
59 Beckett MK, Elliott MN, Clemens JQ, Ewing B, Berry SH. Consequences
of interstitial cystitis/bladder pain symptoms on women’s work participation
and income: results from a national household sample. J. Urol. 2014; 191:
83–8.
60 Nickel JC, Tripp DA, Pontari M et al. Interstitial cystitis/painful bladder syn-
drome and associated medical conditions with an emphasis on irritable bowel
syndrome, fibromyalgia and chronic fatigue syndrome. J. Urol. 2010; 184:
1358–63.
61 Kim SH, Oh SA, Oh SJ. Voiding diary might serve as a useful tool to under-
stand differences between bladder pain syndrome/interstitial cystitis and over-
active bladder. Int. J. Urol. 2014; 21: 179–83.
62 Wennevik GE, Meijlink JM, Hanno P, Nordling J. The role of glomerulations
in bladder pain syndrome: a review. J. Urol. 2016; 195: 19–25.
63 Kuo HC. Potential urine and serum biomarkers for patients with bladder pain
syndrome/interstitial cystitis. Int. J. Urol. 2014; 21(Suppl 1): 34–41.
64 Friedlander JI, Shorter B, Moldwin RM. Diet and its role in interstitial cysti-
tis/bladder pain syndrome (IC/BPS) and comorbid conditions. BJU Int. 2012;
109: 1584–91.
65 Hsieh CH, Chang WC, Huang MC et al. Hydrodistention plus bladder train-
ing versus hydrodistention for the treatment of interstitial cystitis. Taiwan J.
Obstet. Gynecol. 2012; 51: 591–5.
66 FitzGerald MP, Payne CK, Lukacz ES et al. Randomized multicenter clinical
trial of myofascial physical therapy in women with interstitial cystitis/painful
bladder syndrome and pelvic floor tenderness. J. Urol. 2012; 187: 2113–8.
67 Ginting JV, Tripp DA, Nickel JC, Fitzgerald MP, Mayer R. Spousal
support decreases the negative impact of pain on mental quality of life in
women with interstitial cystitis/painful bladder syndrome. BJU Int. 2011;
108: 713–7.
68 Lee MH, Wu HC, Lin JY, Tan TH, Chan PC, Chen YF. Development and
evaluation of an E-health system to care for patients with bladder pain syn-
drome/interstitial cystitis. Int. J. Urol. 2014; 21(Suppl 1): 62–8.
69 Nickel JC, Herschorn S, Whitmore KE et al. Pentosan polysulfate sodium for
treatment of interstitial cystitis/bladder pain syndrome: insights from a ran-
domized, double-blind, placebo controlled study. J. Urol. 2015; 193: 857–62.
70 Foster HE Jr, Hanno PM, Nickel JC et al. Effect of amitriptyline on symp-
toms in treatment naive patients with interstitial cystitis/painful bladder syn-
drome. J. Urol. 2010; 183: 1853–8.
71 Forrest JB, Payne CK, Erickson DR. Cyclosporine A for refractory interstitial
cystitis/bladder pain syndrome: experience of 3 tertiary centers. J. Urol.
2012; 188: 1186–91.
72 Ueda Y, Tomoe H, Takahashi H et al. Interstitial cystitis associated with pri-
mary Sjogren’s syndrome successfully treated with a combination of tacroli-
mus and corticosteroid: a case report and literature review. Mod. Rheumatol.
2016; 26: 445–9.
© 2016 The Japanese Urological Association
Clinical guidelines for IC and HSB
73 Tomoe H. In what type of interstitial cystitis/bladder pain syndrome is
DMSO intravesical instillation therapy effective? Transl. Androl. Urol. 2015;
4: 600–4.
74 Parsons CL, Zupkas P, Proctor J et al. Alkalinized lidocaine and heparin pro-
vide immediate relief of pain and urgency in patients with interstitial cystitis.
J. Sex. Med. 2012; 9: 207–12.
75 Nomiya A, Naruse T, Niimi A et al. On- and post-treatment symptom relief
by repeated instillations of heparin and alkalized lidocaine in interstitial cysti-
tis. Int. J. Urol. 2013; 20: 1118–22.
76 Engelhardt PF, Morakis N, Daha LK, Esterbauer B, Riedl CR. Long-term
results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial
cystitis. Int. Urogynecol. J. 2011; 22: 401–5.
77 Nickel JC, Egerdie RB, Steinhoff G, Palmer B, Hanno P. A multicenter,
randomized, double-blind, parallel group pilot evaluation of the efficacy and
safety of intravesical sodium chondroitin sulfate versus vehicle control in
patients with interstitial cystitis/painful bladder syndrome. Urology 2010; 76:
804–9.
78 Kuo HC, Jiang YH, Tsai YC, Kuo YC. Intravesical botulinum toxin-A
injections reduce bladder pain of interstitial cystitis/bladder pain syndrome
refractory to conventional treatment – a prospective, multicenter, randomized,
double-blind, placebo-controlled clinical trial. Neurourol. Urodyn. 2015; doi:
10.1002/nau.22760.
79 Akiyama Y, Nomiya A, Niimi A et al. Botulinum toxin type A injection for
refractory interstitial cystitis: a randomized comparative study and predictors
of treatment response. Int. J. Urol. 2015; 22: 835–41.
80 Lee CL, Kuo HC. Intravesical botulinum toxin a injections do not benefit
patients with ulcer type interstitial cystitis. Pain Physician. 2013; 16: 109–16.
81 Pinto R, Lopes T, Costa D et al. Ulcerative and nonulcerative forms of blad-
der pain syndrome/interstitial cystitis do not differ in symptom intensity or
response to onabotulinum toxin A. Urology 2014; 83: 1030–4.
82 Cox M, Klutke JJ, Klutke CG. Assessment of patient outcomes following
submucosal injection of triamcinolone for treatment of Hunner’s ulcer sub-
type interstitial cystitis. Can. J. Urol. 2009; 16: 4536–40.
83 Niimi A, Nomiya A, Yamada Y et al. Hydrodistension with or without fulgu-
ration of hunner lesions for interstitial cystitis: long-term outcomes and prog-
nostic predictors. Neurourol. Urodyn. 2015; doi: 10.1002/nau.22837.
84 Marinkovic SP, Gillen LM, Marinkovic CM. Minimum 6-year outcomes for
interstitial cystitis treated with sacral neuromodulation. Int. Urogynecol. J.
2011; 22: 407–12.
85 Gajewski JB, Al-Zahrani AA. The long-term efficacy of sacral neuromodula-
tion in the management of intractable cases of bladder pain syndrome:
14 years of experience in one centre. BJU Int. 2011; 107: 1258–64.
86 O’Hare PG 3rd, Hoffmann AR, Allen P, Gordon B, Salin L, Whitmore K.
Interstitial cystitis patients’ use and rating of complementary and alternative
medicine therapies. Int. Urogynecol. J. 2013; 24: 977–82.
87 Tanaka T, Nitta Y, Morimoto K et al. Hyperbaric oxygen therapy for painful
bladder syndrome/interstitial cystitis resistant to conventional treatments:
long-term results of a case series in Japan. BMC Urol. 2011; 11: 11.
88 Gallego-Vilar D, Garcia-Fadrique G, Povo-Martin I, Salvador-Marin M,
Gallego-Gomez J. Maintenance of the response to dimethyl sulfoxide treatment
using hyperbaric oxygen in interstitial cystitis/painful bladder syndrome: a
prospective, randomized, comparative study. Urol. Int. 2013; 90: 411–6.
89 Payne RA, O’Connor RC, Kressin M, Guralnick ML. Endoscopic ablation of
Hunner’s lesions in interstitial cystitis patients. Can. Urol. Assoc. J. 2009; 3:
473–7.
90 Hillelsohn JH, Rais-Bahrami S, Friedlander JI et al. Fulguration for Hunner
ulcers: long-term clinical outcomes. J. Urol. 2012; 188: 2238–41.
91 Chennamsetty A, Khourdaji I, Goike J, Killinger KA, Girdler B, Peters KM.
Electrosurgical management of Hunner ulcers in a referral center’s interstitial
cystitis population. Urology 2015; 85: 74–8.
92 Kim HJ, Lee JS, Cho WJ et al. Efficacy and safety of augmentation ileo-
cystoplasty combined with supratrigonal cystectomy for the treatment of
refractory bladder pain syndrome/interstitial cystitis with Hunner’s lesion. Int.
J. Urol. 2014; 21(Suppl 1): 69–73.
93 Sun Y, Fang Z, Ding Q, Zheng J. Effect of amitriptyline in treatment inter-
stitial cystitis or bladder pain syndrome according to two criteria: does
ESSIC criteria change the response rate? Neurourol. Urodyn. 2014; 33:
341–4.
549