Role of inflammation in bladder function and interstitial cystitis

Abstract

Cystitis, or inflammation of the bladder, has a direct effect on bladder function. Interstitial cystitis is a syndrome characterized by urinary bladder pain and irritative symptoms of more than 6 months duration. It commonly occurs in young to middle-aged women with no known cause and in fact represents a diagnosis of exclusion. Many factors have been suggested, including chronic or subclinical infection, autoimmunity and genetic susceptibility, which could be responsible for initiating the inflammatory response. However, a central role of inflammation has been confirmed in the pathogenesis of interstitial cystitis. Patients with interstitial cystitis are usually managed with multimodal therapy to break the vicious cycle of chronic inflammation at every step. Patients who develop irreversible pathologies such as fibrosis are managed surgically, which is usually reserved for refractory cases.

Bladder inflammation

Cystitis, or inflammation of the bladder, has a direct effect on bladder function. It can occur due to both infectious as well as noninfectious etiologies. Infections can be due to Gram-negative microorganisms such as Proteus, Klebsiella, Citrobacter, Enterobacter, and Pseudomonas species and Gram-positive pathogens such as Enterococcus fecalis, Staphylococcus saprophyticus, and group B streptococci. However, Escherichia coli represents the most common cause of infectious cystitis [Echols et al. 1999]. Noninfectious cystitis can be due to a variety of causes, such as medication, radiation, foreign bodies, chemicals, autoimmune response, and may even be idiopathic in nature such as interstitial cystitis (IC); it may also occur in association with other diseases such as, gynecological cancer, PID, and Crohn’s disease. Irrespective of the cause, cystitis can be acute or chronic depending upon the duration of the insult.

The first and early response to any noxious stimulus or injury occurs in the form of acute inflammation. Acute inflammation is characterized by vasodilation and increased vascular permeability, leukocyte migration to the site of injury, and activation of biochemical cascade of inflammation causing release of mediators such as cytokines, histamines, kinins, complement factors, clotting factors, nitric oxide, and proteases. In the case of acute cystitis these mediators cause erythematous swelling and ulceration of the bladder mucosa, which bleeds easily. The surface layer is shred, forming small, clear cysts (sacs with liquid, gas, or semisolid contents) frequently seen on urine analysis. In addition, these mediators cause bladder mucosal irritation, which is responsible for urgency, increased frequency, and dysuria. The systemic release of inflammatory mediators causes low-grade fever. In general, these mediators have a short half-life and are quickly degraded, therefore enabling rapid resolution of inflammation as soon as the noxious stimulus is removed. However, if the stimulus is not removed, chronic inflammation ensues, such as seen in IC. This is characterized by infiltration of mononuclear cells such as macrophages, lymphocytes, eosinophils, mast cells, and plasma cells leading to irreversible tissue destruction, dysfunctional pathology such as fibrosis and poor compliance, detrusor overactivity, and hyperalgesia responsible for the chronic waxing and waning symptoms of pain and lower urinary tract symptoms. In this review we limit our discussion to the effects of chronic inflammatory disease such as IC on bladder function.

Interstitial cystitis

IC is a syndrome characterized by urinary bladder pain and irritative symptoms of more than 6 months duration. It commonly occurs in young to middle-aged women with no known cause and in fact represents a diagnosis of exclusion. Over 1 million people are affected by IC in the United States alone [Hanno, 2002; Jones and Nyberg, 1997], in fact; an office survey indicated that 575 in every 100,000 women have IC [Rosenberg and Hazzard, 2005]. Another study on self-reported adult IC cases in an urban community estimated its prevalence to be approximately 4% [Ibrahim et al. 2007]. Children and adolescents can also have IC [Shear and Mayer, 2006]; patients with IC have had 10 times higher prevalence of bladder problems as children than the general population [Hanno, 2007].

The constellation of IC symptoms has been given different names. The International Continence Society named the disease interstitial cystitis/painful bladder syndrome (IC/PBS) in 2002 [Abrams et al. 2002], while the Multinational Interstitial Cystitis Association have labeled it as painful bladder syndrome/interstitial cystitis (PBS/IC) [Hanno et al. 2005]. Recently, the European Society for the study of Interstitial Cystitis (ESSIC) proposed the moniker, ‘bladder pain syndrome’ (BPS) [van de Merwe et al. 2008].

Etiology

The precise etiology of IC is still unknown. Many factors have been suggested, including chronic or subclinical infection, autoimmunity, and genetic susceptibility, which could be responsible for initiating the inflammatory response.

Infection

Earlier, bacterial infection was thought to be the main cause of the changes observed in IC. Wilkins and colleagues suggested that fastidious bacteria such as Gardnerella vaginalis and Lactobacillus may be responsible for development of IC [Wilkins et al. 1989]. Domingue and colleagues demonstrated the presence of bacterial 16S rRNA genes in bladder tissue in 29% of patients with IC [Domingue et al. 1995]. However, several other studies failed to confirm this finding, and it is now generally accepted that infection does not represent the etiology behind IC.

Autoimmunity

An increased number of CD8+ and CD4+ T lymphocytes [MacDermott et al. 1991], plasma cells, and immunoglobulins such as IgG, IgA, and IgM [Christmas, 1994] are detected within the urothelium and lamina propria layer of the bladder in IC compared with normal bladders. However, no consistent profile of immune activity has been reported so there remains significant doubt about whether these findings are causative or a reaction to the cause.

Environmental factors

Studies have also shown worsening of IC symptoms with stress, spicy food, and smoking. Recently, the Events Preceding IC Study reported that the pain in 97% worsened with certain foods and drinks such as alcohol, citrus fruits, coffee, carbonated drinks, tea, chocolate, and tomatoes [Warren et al. 2008] comparable to findings from the Interstitial Cystitis Database (ICDB) where 262 out of 270 (97%) patients reported worsening of pain [Simon et al. 1997].

Association with other diseases

IC patients also been shown to have a higher incidence of other comorbid diseases [Peeker et al. 2003; Aaron and Buchwald, 2001; Erickson et al. 2001; Alagiri et al. 1997; Koziol et al. 1993] including allergies (in roughly 40–60% of patients) [Stanford et al. 2005; Yamada, 2003], fibromyalgia, irritable bowel syndrome (IBS; 35% cases) [Novi et al. 2005], vulvodynia (20–51.4% of patients) [Peters et al. 2008; Stanford et al. 2005], endometriosis, panic disorders, and inflammatory bowel disease (IBD), particularly in patients with Hunner’s ulcers [Peeker et al. 2003; Alagiri et al. 1997].

Genetic link

Studies have shown that IC is more common in twins with chronic fatigue syndrome. Recently, Warren and colleagues studied the prevalence of IC in first-degree relatives of patients with IC, reporting that adult female first-degree relatives have a prevalence of IC 17 times greater that found in the general population [Warren et al. 2004]. They also studied the prevalence of IC in monozygotic and dizygotic twins, reporting a greater concordance of IC among monozygotic compared with dizygotic twins, suggesting a genetic contribution to IC [Warren et al. 2001].

Pathophysiology and role of inflammation in the presentation of IC

Many theories have been suggested to exemplify the pathogenesis behind IC. However, a central role of inflammation has been confirmed in both human and animal studies using electron microscopy and immunohistochemical staining techniques. Irrespective of the etiology, if the noxious stimulus persists for a longer duration, it leads chronic inflammation. As a result, a cascade of events, which are interrelated with each other is initiated, resulting in a vicious, self-reinforcing cycle of persistent inflammation and recurrent injury to bladder epithelium [Sant et al. 2007] (Figure 1).

Figure 1.

Integrated pathophysiology of interstitial cystitis. (Reproduced with permission from Sant et al. [2007]).

Dysfunctional urothelium

The urothelium is covered by a layer of glycosaminoglycans chondroitin sulfate, hyaluronate sodium, glycoproteins, and mucins to protect the bladder [Hanno, 2007]. In IC damage occurs to the mucous or glycosaminoglycans layer, causing altered permeability of the urothelium to various urinary cations such as potassium. Damage also occurs to the urothelium after an initial insult, followed by cytokine production, leading to the proliferation and activation of mast cells [Theoharides et al. 2001]. Influx of potassium ions causes upregulation of sensory afferent nerves, which further activates the mast cells, thus initiating a vicious, self-reinforcing cycle [Parsons et al. 1998; Lilly and Parsons, 1990]. In addition, studies have suggested that the urothelium releases a number of neuropeptides (e.g. nerve growth factor) neurotransmitters and antiproliferative factor (APF), which activates submucosal afferent nerves and mast cells during this process [Theoharides et al. 2001] resulting in hyperalgesia in patients with IC. APF induces increased permeability of normal urothelium and regulates expression of other cytokines, such as upregulating heparin-binding epidermal growth factor-like growth factor and downregulating epidermal growth factor, by the urothelium. These cytokine abnormalities could mediate increased bladder sensation and pain [Graham and Chai, 2006].

Mastocytosis and mast cell activation

An increased number of mast cells, both in submucosa and detrusor layers [Johansson and Fall, 1990], can be seen particularly in classic IC with Hunner’s ulcers. A study using immunocytochemical techniques demonstrated a 6- to 10-fold increase in mast cells in classic/ulcerative IC compared with a 2-fold increase in patients with nonulcerative IC [Peeker et al. 2000b]. Recent studies have shown that a diagnostic cutoff of mast cell counts >20 cells/mm² in bladder muscle have 95% diagnostic sensitivity with 88% diagnostic specificity for IC [Kastrup et al. 1983].

Mast cells are activated by numerous mediators such as: (1) cytokines-like stem cell factor (SCF) [Peeker et al. 2000b; Pang et al. 1998] that are released by damaged urothelium or nerve growth factor (NGF) [Lowe et al. 1997], which is also increased in patients with IC; (2) bacterial and viral super antigens; (3) immunoglobulin aggregates; (4) neuropeptides, such as substance P (SP) [Theoharides et al. 2001]; (5) acetylcholine (ACh) [Theoharides et al. 2001]; and (6) neurotensin. Once activated, mast cells undergo degranulation to release vasoactive, inflammatory, and nociceptive mediators, such as histamine, kinins, proteases (e.g. tryptase), cytokines, leukotrienes (e.g. IL-6 and IL-8), prostaglandins, and nitric oxide [Cao et al. 2005; Sant and Theoharides, 1994]. For example, vascular endothelial growth factor (VEGF) is overexpressed in 58% of IC bladders [Tamaki et al. 2004], while IL-6 and IL-8 are also overexpressed. The release of vasoactive and inflammatory mediators from mast cells may explain many IC symptoms. Tryptase can cause microvascular leakage [He and Walls, 1997] and stimulate protease-activated receptors (PARs), in turn leading to widespread inflammation and neuronal hyperexcitability [Theoharides and Cochrane, 2004]. Mast cell-derived tumor necrosis factor-α (TNF-α) activates the nuclear transcription factor-κB [Batler et al. 2002; Rackley et al. 1999], which is a key regulator of inflammatory gene expression, causing further urothelial inflammation. VEGF, another mast cell mediator, causes vasodilation and may therefore be responsible for the hypervascularity and glomerulations, which are characteristic of IC [Tamaki et al. 2004]. Studies have also shown an association between increased VEGF and severity of IC-associated pain [Kiuchi et al. 2009]. Usually, these mediators have shorter half-life, but in IC the noxious stimulus persists for a longer duration resulting in increased secretion of inflammatory mediators even when the stimulus is removed. This causes angioedema leading to vasculitis and neuroinflammation, which promote neuritis and secretion of neurotransmitters that further stimulate mast cells. Therefore, a vicious circle of events begins, causing persistent inflammation and urothelial re-injury, which clinically manifests as hyperalgesia leading to dysuria, urgency and lower urinary tract symptoms.

Neuronal inflammation and nerve upregulation

It is believed that IC also represents a visceral neuropathic pain syndrome mediated by upregulation of nerves in the pelvis, spinal cord, and brain. The vasoactive and inflammatory molecules, such as SP and NGF, secreted by mast cells potentially increase proliferation of the nerve fibers [Theoharides et al. 1995]. Studies have shown that there is an increase in nerve fibers in IC, particularly those containing the neuropeptide SP in patients with untreated IC [Pang et al. 1995b]. Perivascular sensory nerve terminals have been found to have enhanced sensitivity to SP leading to a local cascade of neurogenic inflammatory responses, which is responsible for the pathophysiological changes of IC [Marchand et al. 1998; Parsons et al. 1980]. This potentially explains the flaring of symptoms in female patients with IC before menses due to an estrogen surge that induces histamine release from mast cells with subsequent secretion of SP [Pang et al. 1995a]. Likewise, stress may exacerbate IC symptoms due to release of corticotropin-releasing factor (CRF) and subsequent activation of mast cells [Theoharides et al. 2004, 1998]. The increased levels of NGF and morphological changes (neuroplasticity) in sensory and motor neurons may be responsible for continued pain, frequency, and urgency even after the initial inflammatory stimulus has subsided.

An increased sensitivity of bladder sensory afferents may also be responsible for increased pain sensation or hyperalgesia [Dmitrieva et al. 1997; Cervero, 1994; Eide et al. 1993; Dubner and Ruda, 1992]. Pelvic and hypogastric/lumbar splanchnic nerve innervations of the bladder contain mechanosensitive Aδ and C-fibers that also respond to chemical and thermal stimuli, particularly after sensitization. These nerve fibers are found in serosa, muscle, and urothelium. As bladder volume increases, the threshold for mechanosensitive endings, which encode for changes in volume, decreases, leading to activation and discharge of these fibers at a lower bladder volume causing urgency. Numerous other mediators have also been identified in modification of this afferent pathway including SP, neurokinin A, calcitonin gene related protein (CGRP), vasoactive intestinal peptide, and enkephalins [Cervero, 1994].

The effect of local hypersensitivity reflected on the peripheral and/or central nervous systems

Hypersensitivity to nonpainful and normally painful stimuli causes an increased input from sensitized bladder afferents which in turn stimulates the release of neuroactive chemicals in the spinal cord dorsal horn, leading to central (spinal) hyperexcitability [Mayer and Gebhart, 1994]. Various mediators, including glutamate, SP, and CGRP released from the central terminals of primary afferent fibers, are involved in central sensitization [Ruda and Dubner, 1992]. N-methyl-D-aspartate (NMDA) and NO receptors have been identified in spinal dorsal horn neurons, may also have a role [Traub et al. 1992; Woolf and Thompson, 1991; Davies and Lodge, 1987]. This brings about changes in gene expression and neurotransmitter synthesis causing a state of neurologic ‘wind up’ manifested by visceral allodynia and hyperalgesia in the bladder and adjacent pelvic organs (gastrointestinal, gynecologic) such as dyspareunia, vulvodynia, and IBS.

These changes in urothelial permeability, urothelial activation, sensory nerve stimulation, and mast cell activation are complex and are interrelated with multiple, simultaneous positive and negative feedback loops. This vicious circle is responsible for the irreversible dysfunctional pathology such as fibrosis and poor compliance, detrusor overactivity, and hyperalgesia responsible for the chronic waxing and waning symptoms of pain and lower urinary tract symptoms.

Presentation and diagnosis

Since IC can have a very heterogeneous clinical presentation, it is grouped according to the pathologic features as classic (ulcerative) versus non ulcerative cystitis, mild vs. severe inflammation with the degree and location of mast cell activation described.

IC as described originally by Hanash and Pool is characterized by urinary symptoms of severely reduced bladder capacity and cystoscopic findings of Hunner’s ulcers [Hunner, 1918], which are patches of reddened mucosa exhibiting small vessels radiating to a central pale scar [Hanash and Pool, 1969]. However, the more frequent presentation of IC is the nonulcerative variety, which is characterized by glomerulation and submucosal hemorrhages.

In the past, clinicians have relied on the criteria proposed by the National Institutes of Arthritis Diabetes Digestive and Kidney Diseases (NIDDK) for the diagnosis of IC [Wein et al. 1990]. These stringent criteria were originally designed for research purposes and in fact based on a consensus of expert opinion, not clinical evidence. Recent studies have shown that relying on the NIDDK criteria may result in the misdiagnosis in 60% of patients who definitely or likely had IC by clinical criteria [Abrams et al. 2006; Kusek and Nyberg, 2001]. It is now widely accepted that the diagnosis of IC should be based on symptoms along with the exclusion of similar conditions such as, pelvic pain, urinary tract infection (UTI), yeast infections, endometriosis, pelvic organ prolapse, gynecological or urological malignancies, overactive bladder, and chronic prostatitis (Figure 2).

Figure 2.

Algorithm for the management of patients with chronic pelvic pain. GnRH, gonadatrophin-releasing hormone; IBS, irritable bowel syndrome; OC, oral contraceptives.

In 2002, the International Incontinence Society (ICS) revised the definition of PBS an effort towards diagnosis standardization [Abrams et al. 2002]. PBS 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 urinary infection or other obvious pathology. Recently, the European Society for the Study of Interstitial Cystitis (ESSIC) [van de Merwe et al. 2008] defined IC as chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder and accompanied by at least one other urinary symptom such as persistent urge to void or urinary frequency. Further, tests such as biopsy or cystoscopy with hydrodistention are not necessary for the diagnosis of IC, but may help to classify the types of IC.

Patients with IC may also experience flares with seasonal allergies and sexual intercourse [Parsons, 2002]. Voiding typically relieves pain [Metts, 2001], and as such, patients may void frequently in small volumes to relieve pain as the bladder fills. Patients with IC are more likely to be diagnosed with other accompanying diseases such as IBS [Novi et al. 2005; Alagiri et al. 1997; Koziol, 1994], IBD, allergies, fibromyalgia, and systemic lupus erythematosus (SLE) [Alagiri et al. 1997]. A voiding diary may be helpful to establish frequency, nocturia, and the presence of triggers such as allergies, certain foods, and/or intercourse [Nickel, 2004]. Symptom screeners such as the pelvic pain and urgency/frequency (PUF) questionnaire and the O’Leary–Sant IC symptom and problem indices can also be used in obtaining this information [Parsons et al. 2002a; O'Leary et al. 1997]. Tenderness of the urethra and bladder base on single-digit examination is typical of IC.

Laboratory studies are used to help distinguish IC from other similar conditions. Urinalysis should be done to rule out hematuria, and urine culture should be performed to identify bladder infection [Butrick, 2003; Nickel, 2000]. Cytology and CT scan with noncontrast, arterial, and delayed phase imaging should be performed whenever there is history of smoking, hematuria, and/or age >40 years, to rule out urinary tract malignancies [Ottem and Teichman, 2005]. Cystoscopy with or without hydrodistention can be helpful to confirm IC [Ottem and Teichman, 2005; Metts, 2001]. Glomerulations may be present, although these may also be present in subjects with no symptoms of IC [Waxman et al. 1998]. Hunner’s ulcers can also be seen in patients with IC; a negative cystoscopic evaluation, however, should not be used to rule out IC as many patients with early IC do not have glomerulations or Hunner’s ulcers [Ottem and Teichman, 2005]. Several other optional diagnostic tests also exist to help define the diagnosis of IC, such as the potassium sensitivity test (PST), anesthetic bladder challenge (ABC), bladder biopsy, urodynamic testing, and assessment of urinary markers. A positive PST, for example, can be indicative of a defective bladder lining, consistent with IC. The PST involves intravesical instillation of a potassium solution, which triggers symptoms of pain and urgency in patients with abnormal bladder surface permeability [Teichman and Nielsen-Omeis, 1999]. The ABC can be performed for patients who present with pain of suspected bladder origin; the patient is catheterized and an intravesical anesthetic cocktail containing alkalinized lidocaine is administered. Dissipation of pain upon instillation confirms that the bladder is the site of origin of the pain [Evans and Sant, 2007]. Bladder biopsy is advised when a lesion is found, to rule out carcinoma in situ, for example [Sant, 2002]. Although, urodynamic testing is not required for a diagnosis of IC, it may help rule out other bladder disorders such as detrusor instability, stress urinary incontinence, and bladder outlet obstruction [Nickel, 2004; Sant and Hanno, 2001]. Miscellaneous tests such as evaluation of urinary markers, such as, eosinophil cationic protein, glycoprotein-51, and APF can also be performed [Erickson, 2001]. Of these, the activity of APF, is specific and selective (>90%) for patients with IC compared with matched control patients (p < 0.005) [Erickson, 2001]. APF inhibits the proliferation of primary human bladder epithelial cells by downregulating growth factors, which are involved in the pathogenesis of IC [Keay et al. 2000].

Management

From our current understanding of chronic bladder inflammation, there are many steps in the pathogenesis, which can be targeted during treatment selection. As such, a multimodal treatment regimen with oral therapies, intravesical therapies, complementary therapies that utilize anti-inflammatory, neural, anesthetic, and behavioral agents as well as others, is our current approach. Finally, surgical techniques can be used as a last resort to structurally alter, modify, or remove the source of pain. Studies have shown that many patients respond well to treatment strategies that use a variety of pharmacological and nonpharmacological approaches [Nickel et al. 2005; Evans, 2002]. In chronic bladder inflammation, the concept of a cyclical process is often proposed, with the idea that if one breaks the cycle of recurrence, it will lead to healing. As such, treatment is directed at the urothelial layer, nervous system, immune system to break the cycle of pain at various steps (Figure 3).

Figure 3.

The cycle of interstitial cystitis: treatment directed at the urothelial layer, nervous system, and immune system to break the cycle of pain at various steps.

Nonpharmacological approaches

Nonpharmacological approaches involve techniques that the patients may use to reduce the severity of IC symptoms, such as stress and anxiety reduction, exercise and physical therapy, sex therapy and counseling, bladder training, pelvic floor rehabilitation training, and dietary changes [Nickel, 2004; Butrick, 2003]. Physical therapy techniques, such as biofeedback to control pelvic floor dysfunction [Whitmore, 2002], soft tissue massage including myofascial release, and bladder retraining are commonly used in patients with little or no pain [Whitmore, 1994]. Intensive physical therapy should be used at the outset of symptoms and repeated at least once a year to maintain benefit.

As a latency period between the start of the treatment and the relief of symptoms is common, reassurance and management of the patient expectations regarding IC is critical to main adherence to their treatment plan [Evans, 2002].

Pharmacological approaches

Oral medications

Bladder mucosal protectors

1. Pentosan polysulphate (Elmiron). Pentosan polysulphate acts by coating the bladder lining and re-establishing the normal glycosaminoglycan (GAG) layer function [Moldwin and Sant, 2002]. Parsons and colleagues conducted a double-blind multicenter study where IC patients who were treated with pentosan polysulphate showed improvement in their symptoms [Parsons et al. 2002b].

Anti-allergics

1. Antihistamines. Since mast cells and their mediators such as histamine are the key players in the inflammation and pathogenesis of IC [Moldwin and Sant, 2002], therapy that blocks the effect of histamine have been shown to improve symptoms. These include the H1 blocker hydroxyzine hydrochloride [Moldwin and Sant, 2002] as well as H2 blockers such as cimetidine which have shown to produce significant improvement in pain and nocturia in a limited trial of IC patients [Thilagarajah et al. 2001].

2. Leukotriene-D4 receptor antagonist montelukast. The presence of leukotriene receptors in detrusor muscle cells [Bouchelouche et al. 2001a] and an increased urinary level of leukotriene E4 in IC patients suggests a role for these pro-inflammatory mediators in IC. Bouchelouche and colleagues reported their experience in 10 women with IC [Bouchelouche et al. 2001b], who were treated with the leukotrine antagonist montelukast. They found that after 1 month of montelukast treatment, there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain, which persisted during the 3 months of treatment. After 3 months, 24-hour urinary frequency decreased from 17.4 to 12 voidings (p = 0.009), nocturia decreased from 4.5 to 2.8 (p = 0.019) and, pain decreased from 46.8 to 19.6 mm on a visual analog scale (p = 0.006). There were no side effects observed during the treatment.

Pain modulators

1. Tricyclic antidepressants. Amitriptyline has been shown to be effective in the management of chronic pain syndromes, including IC [Hanno, 1994]. Amitriptyline modulates the transmission of nociceptive stimuli by inhibiting the presynaptic reuptake of serotonin and noradrenaline [Tura and Tura, 1990]. Amitriptyline has been found to be beneficial in a controlled trial for IC with long-term follow up using a stepwise dose escalation, and is reported to cause 50% reduction in pain and daytime frequency [Hanno et al. 1989]. Recently, a randomized, double-blind, placebo-controlled clinical trial of amitriptyline in 44 women and 6 men with IC that used a self-titration protocol (up to 100 mg/day at bedtime for 4 months) reported a significant improvements in all symptoms [van Ophoven et al. 2004]. In another study, long-term follow up of 60 patients treated with amitriptyline for 19 ± 12.5 months was associated with a response rate of 64% using the Global Response Assessment [van Ophoven and Hertle, 2005].

2. Anticonvulsants. Anticonvulsants such as gabapentin often are prescribed for neuropathic pain [Lukban et al. 2002; Hansen, 2000]. These drugs can be used to treat patients with refractory IC who have failed to respond to other treatments [Butrick, 2003].

Hormone modulators

1. Leuprolide acetate. Many women of reproductive age with IC often complain of worsening symptoms during their menstrual cycle [Powell-Boone et al. 2005]. This may be related to the fact that estradiol activates the estrogen receptors expressed on bladder mast cells, which in turn increases pro-inflammatory molecule secretion [Spanos et al. 1996]. Leuprolide acetate may be useful in such cases, as it is a gonadotropin-releasing hormone agonist causing a reduction in estradiol secretion. In 15 female patients with irritable bladder symptoms and pelvic pain without endometriosis, symptoms improved in eight of nine patients treated with leuprolide acetate and in five of six patients treated with oral contraceptives [Lentz et al. 2002]. The estrogen receptor antagonist has shown to significantly increase the mean maximum bladder volume by over 70% in rat chemical cystitis model [Acar et al. 2007].

Anti-inflammatory

1. Anti-TNF therapy. Recently, various research studies have focused on the neuro-inflammatory mechanism of pain to further target specific areas for therapy. A hypothetical model of a cholinergic anti-inflammatory pathway, based on bacterial LPS as a stimulant, has been proposed and therapies are being developed to specifically target and disrupt this neuro-inflammatory loop such as anti-NGF to lower SP, or anti-TNF-α or neuromodulation to break the loop and provide relief [Saini et al. 2008].

Animal studies have reported that a virus-induced neurogenic inflammation can lead to a 20-fold increase in degranulated mast cells in the lamina propria, that is primarily dependent on TNF-α [Chen et al. 2006]. In addition, TNF-α can promote mast cell trafficking and induce urothelial inflammation [Batler et al. 2002]. These findings have prompted the suggestion of a possible use for anti-TNF therapy, although no clinical data for its use exists.

2. Narcotics and pain relief. Most IC patients experience chronic pain, albeit to various extents. The pain could be managed with opioids either alone or in combination with hydroxyzine to increase the analgesic response and decrease adverse effects [Hupert et al. 1980]. Tramadol, with fewer adverse effects than those of morphine, either alone or together with acetaminophen (37.5/325 mg twice daily), may be helpful.

3. Immunosuppressive agents. Immunosuppressive agents may be used as second-line therapy in IC. Prednisone for example may be used in treatment refractory cases [Soucy and Gregoire, 2005]. Thirty patients with Hunner’s ulcer subtype IC showed considerable improvement following endoscopic submucosal injection of triamcinolone [Cox et al. 2009]. Other drugs such as cyclosporine have also been shown to relieve the symptoms of severe IC [Sairanen et al. 2005; Forsell et al. 1996]. In an open-label study in 11 patients with intractable IC, cyclosporine treatment for up to 6 months reduced micturition, urinary frequency, and bladder pain significantly in most of the patients [Forsell et al. 1996]. Recently, in a randomized study on 64 patients with IC that met NIDDK criteria, patients were treated with either cyclosporine or pentosan polysulfate for 6 months. The clinical response rate was determined using the Global Response Assessment and was found to be 75% for cyclosporine, compared with 19% for pentosan polysulfate (p < 0.001) [Sairanen et al. 2005].

Others

1. L-arginine. Patients with IC have decreased urine nitric oxide synthase and urine nitric oxide levels [Hosseini et al. 2004]. These patients respond to treatment with oral L-arginine, a precursor in nitric oxide synthesis. In one randomized, double-blind, placebo-controlled study, 21 out of 27 IC patients received 1500 mg of L-arginine for 3 months and were compared with 25 out of 26 patients on placebo: a greater global improvement in the L-arginine group (48%, 10 of 21) compared with the placebo group (24%, 6 of 25) at 3 months (p = 0.05) with a decrease in pain intensity (p = 0.04), and tendency toward improvement in urgency (p = 0.06) and frequency of pain (p = 0.09) were noticed [Korting et al. 1999]. In another randomized, double-blind, crossover study using 2.4 g of L-arginine in 16 IC patients for 1 month, there was a reduction of 2.2 in overall symptom score, but no significant difference in voided volume, frequency, or nocturia [Cartledge et al. 2000].

2. Anticholinergics. Oxybutynin and tolterodine are commonly used anticholinergic drugs for the treatment of symptoms associated with overactive bladder in IC. They both act mainly on the muscarin-3 (M3) subtype receptor, which causes contraction of bladder detrusor, urgency, and urinary incontinence. Unfortunately, salivary glands also have M3 receptor, and therefore dry mouth is a major side effect especially with oxybutynin [Cannon and Chancellor, 2002]. A long-acting once-a-day formation of tolterodine (Detrol LA) was approved by the US Food and Drug Administration (FDA). Tolterodine LA has fewer side effects and similar or modestly better efficacy than the twice-a-day tolterodine formulation [Van Kerrebroeck et al. 2001]

Intravesical treatment

Pain modulators

1. Dimethylsulfoxide (DMSO). DMSO can have analgesic, anti-inflammatory, collagenolytic, muscle relaxant effects, and in fact represents a standard treatment for IC. In a controlled, crossover trial, 33 patients with IC were allocated randomly to receive 50% DMSO solution or placebo (saline). The medication was administered intravesically every 2 weeks for two sessions of four treatments each. Response was assessed urodynamically and symptomatically. Subjective improvement was noted in 53% of patients receiving DMSO versus 18% receiving placebo and objective improvement in 93% and 35%, respectively [Perez-Marrero et al. 1988].

2. Bacillus Calmette–Guerin (BCG). BCG is most commonly used in the treatment of high-grade recurrent or multifocal bladder cancer. A prospective double-blind, placebo-controlled study with IC patients showed 60% positive response in patients on BCG compared with 27% in patients receiving placebo [Peters et al. 1997]. In another randomized, placebo-controlled, double-blind trial in 260 patients with refractory IC, BCG demonstrated a global response rate of 21% versus 12% for placebo (p = 0.062) [Mayer et al. 2005]. Other multicenter trials are currently under way to determine the role of BCG in the treatment of IC patients.

Bladder mucosal protectors

1. Hyaluronic acid. Intravesical administration of hyaluronic acid is thought to protect the bladder surface and has shown benefit in open clinical studies. Morales and colleagues reported a response rate of 56% at week 4 and 71% at week 7, in 25 patients treated with intravesical instillation of hyaluronic acid [Morales et al. 1996]. After week 24, effectiveness decreased, but there was no significant toxicity.

Others

Other drugs such as chondroitin sulfate, vanilloids, and intravesical botulinum toxin can also be used either alone or can be combined in a cocktail for intravesical instillation. Intravesical therapy is required for patients who do not respond to oral treatments or who experience intolerable side effect [Forrest and Dell, 2007].

Surgical treatment

Surgery is reserved as a last-line therapy when more conservative options have been exhausted.

Bladder distension

While bladder distension can be used as a diagnostic procedure for IC, it can also serve in a therapeutic role [Moldwin and Sant, 2002]. Most patients demonstrated a worsening of symptoms for 2–3 weeks after hydrodistension but then experience symptom relief after that period of time. Glemain and colleagues tested the efficacy of hydrodistension for symptomatic treatment of IC with follow up at 6 and 12 months [Glemain et al. 2002]. Treatment efficacy was reported as 60% at 6 months, declining to 43.3% at 12 months. Erickson and colleagues reported that the median symptom score for newly diagnosed patients decreases after hydrodistention, but only a minority of patients had at least 30% symptom improvement [Erickson et al. 2007].

Transurethral resection of visible ulcers

Transurethral resection (TUR) is reserved only for patients with visible Hunner’s lesions. Fall reported his experience with TURs in 30 patients with classic IC, and found that a complete TUR of all visible lesions resulted in initial disappearance of pain in all, and decreased frequency in 21 patients [Fall, 1985]. Although a relapse was reported in one third of the patients, the remaining two thirds were still free of pain even after 2–20 months. In another study, Peeker and colleagues performed 259 TURs in 103 IC patients [Peeker et al. 2000a]; 92 experienced amelioration, and in 40% symptom relief lasted more than 3 years. In the remaining patients, although symptom recurrence was common, the majority responded well to subsequent TUR.

Laser coagulation

Transurethral ablation of bladder tissue aims to eliminate visible Hunner’s ulcers. Use of the neodymium:yttrium–aluminum–garnet (Nd:YAG) laser has been suggested as an alternative to TUR for patients with IC. Shanberg and colleagues initially treated five patients with refractory IC with the Nd:YAG laser, of whom four demonstrated cessation of pain and frequency within several days [Shanberg et al. 1985]. Follow up at 3–15 months revealed no relapse, with the exception of mild recurrent voiding symptoms.

Neuromodulation

Recently, unilateral sacral nerve (S3) stimulation has emerged as a promising treatment option for IC. Peters demonstrated that IC patients refractory to conventional therapies responded well to sacral nerve stimulation and can maintain this improvement after permanent implantation of a neurostimulator [Peters, 2002]. More recently, Comiter confirmed the positive results with sacral neuromodulation on voiding and pelvic pain in patients with IC [Comiter, 2003].

Cystectomy

When all conservative efforts fail, surgical removal of the diseased bladder represents the last and most extreme treatment option [Moldwin and Sant, 2002]. Three types of cystectomy have been described in the setting of IC: supratrigonal (i.e. trigone-sparing), subtrigonal cystectomy, or radical cystectomy including excision of the urethra. van Ophoven and colleagues, for example, reported their experience with trigone-preserving cystectomy with orthotopic substitution enteroplasty for 18 patients, using ileocecal (n = 10) or ileal (n = 8) segments [van Ophoven et al. 2002]. At 5 years, 14 (77.78%) patients were completely pain free, 12 (66.67%) were able to void spontaneously, while 15 (83.33%) reported complete resolution of dysuria.

Management guidelines

Since IC has a wide range of presentation, management must be individualized. Frequent follow up and patient counseling about disease and expectations from the treatment plays an important role in the management of IC [Kahn et al. 2005]. Management should focus on the treatment of all possible external sources of pain, including endometriosis, fibromyalgia, and vulvodynia [Aaron and Buchwald, 2003; Butrick, 2003]. Regular follow-up visits to monitor patients’ progress and address their concerns are important for optimal outcomes. Treatment plans should be modified based on patient response to therapy.

Conclusion

Inflammation has a direct effect on bladder function. In cases of acute inflammation, for example UTI, the inflammatory mediators are released and cause urothelial injury and bladder wall irritation. These inflammatory changes are responsible for clinical manifestation of urgency, dysuria, frequency, nocturia, and fever. In acute inflammation these changes are short lived and are resolve as soon as the noxious stimulus is removed. If the noxious stimulus persists for a longer duration it leads to chronic inflammation, resulting in recurrent injury to bladder mucosa and other dysfunctional pathologies such as fibrosis. These pathological changes lead to urgency, frequency, dysuria, and cystoscopic findings of Hunner’s ulcers, which are typically seen in IC. Patients with IC are usually managed with multimodal therapy to break the vicious cycle of chronic inflammation at every step. Patients who develop irreversible pathologies such as fibrosis are managed surgically, which is usually reserved for refractory cases.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

None declared.