By Dr. Maria Benito
Interstitial cystitis (IC) was first described as a specific epithelial damage and ulceration, commonly referred to as ‘Hunner’s ulcer’ or lesions. Soon after, two variations of the condition were identified: the ‘classic’ or ulcerative IC was primarily portrayed as a condition characterized by urinary symptoms, markedly reduced bladder capacity, and cystoscopic findings of large irregular lesions –Hunner’s ulcers–, and patches of reddened mucosa with capillaries radiating from a central pale scar; and the ‘non-ulcer’ IC, exemplified by multiple strawberry-like petechial hemorrhages called ‘glomerulations’ and submucosal hemorrhages. Later, bladder pain syndrome (BPS) was defined in 2002 by the International Continence Society as ‘the complaint of suprapubic pain related to bladder filling accompanied by other symptoms such as frequency, in the absence of urinary tract infection and other obvious pathology’.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is therefore a chronic urological condition characterized by a prolonged duration of symptoms of pelvic or perineal pain, thinning of the bladder epithelium, and various voiding symptoms such as nocturia, increased urinary frequency, and urgency that, once diagnosed, is managed with a variety of therapeutic strategies. Histopathologic features present in IC may include chronic inflammation of the bladder as the primary characteristic in a subpopulation of patients.
IC/BPS is a bladder disease that can affect relationships and social life, exercise and sleep, and cause distress. In some cases, this pathology is concomitant with other pathologies and pain syndromes. The most common symptoms include pain, increased urinary frequency that might worsen under physical or mental stress conditions, discomfort, and pain during sexual intercourse.
Epidemiology and Cause
IC/BPS affects 0.06%-30% of the population depending on diagnostic criteria and the population studied, predominantly in the female population with a 10:1 proportion –although in most cases men diagnosed with prostatitis or similar conditions may really have IC/BPS–, without differences in race and ethnicity. There is a high annual cost associated to this pathology, and the risk of IC/BPS intensifies as age increases.
Although the cause of IC/BPS is unknown, some theories for the proposed mechanism point to damage or defects in the bladder lining, histamine released by inflammatory mast cells leading to IC/BPS symptoms, a problem in the pelvic musculature, endocrine, neurological, allergic, and inflammatory system or an autoimmune condition; genetic inheritance might also be involved in the syndrome.
Pathogenesis and Pathologic Findings
Several pathophysiological mechanisms can intervene in the etiology of BPS. A lesion in the bladder can trigger a neural, endocrine and inflammatory response. The exposure of submucosal structures to harmful cytotoxic urinary agents can results in ulcerous and non-ulcerative BPS. The neurogenic inflammation in the peripheral and central nervous systems of BPS patients can lead to the alteration of neuroplasticity and neuronal sensitization.
Two types of this syndrome have been identified: ulcerative –with areas of reddened mucosa associated with small vessels radiating towards a central scar, at times covered by fibrin– and non-ulcerative disease –with initially a normal bladder mucosa, and the development of glomerulations after hydrodistension.
A significant number of patients with ulcerative IC show ulceration –frequently filled with fibrin–, severe inflammation –the lympho-plasmacytic inflammatory infiltrates are usually superficial, and restricted to the edematous and hemorrhagic lamina propria, where mast cells, considered a strong histologic marker for IC, are also abundant–, and granulation tissue. About 80% patients present perineural inflammation. On the other hand, most patients with non-ulcerative IC have little or no inflammation, but edema and vascular congestion are frequently seen.
Recently, investigators have suggested that patients with IC had prominent plasma cell infiltration and fibrosis in the affected bladder tissue, raising the suspicion that IC could be part of a systemic IgG4-related disease.
Irritable bowel syndrome (IBS), allergy, asthma, systemic lupus erythematosus, vulvodynia, sicca syndrome, temporomandibular joint disorder, fibromyalgia, chronic fatigue syndrome (CFS), depression, panic disorders, and migraine are some of the non-bladder syndromes that are associated with BPS, especially with the non-ulcerative variety.
The diagnosis of this condition was originally based on symptoms –bladder pain, urinary urgency–, evidence of supportive bladder pathology on cystoscopy to look for histologic findings –inflammatory infiltrate, granulation tissue, detrusor mastocytosis, intrafascicular fibrosis, and Hunner’s ulcers–, and exclusion of other possible diagnoses.
Currently, there is still no medical test to diagnose IC/BPS other than the symptoms; the diagnosis of BPS is primarily clinical –mostly by exclusion–, therefore it can be subjective. Urodynamic evaluation, cystoscopy and biopsy are used to rule out other pathologies. In the non-ulcer disease pattern, it is possible to observe a normal bladder mucosa at initial cystoscopy, with the subsequent development of glomerulations after hydrodistension, which is considered a definite sign of diagnosis. In the ulcer BPS, areas of the reddened mucosa, associated with small vessels radiating towards a central scar, sometimes covered by a small clot or fibrin deposit are frequently observed.
A list of differential diagnoses to be excluded has been proposed as a guideline by the European Society for the Study of BPS (ESSIC), which entails: infection –including common intestinal bacteria, chlamydia trachomatis, mycoplasma, corynebacteria, herpes simplex virus, and human papillomavirus–, overactive or incompetent bladder, radiation or drug-mediated cystitis, bladder outlet obstruction, urinary tract stones, urethral diverticulum, urogenic prolapse, endometriosis, vaginal candidiasis, gynecologic cancers, prostate cancer, benign prostatic obstruction, chronic bacterial/non-bacterial prostatitis, pudendal nerve entrapment, irritable bowel syndrome, diverticular disease, and pelvic floor muscle-related pain.
Markers of IC/BPS
The inflammatory urinary markers –mast cells, histamine, methylhistamine, IL-6, CRP, CXCL10, CXCR3, TNFSF14, Th chemokine, tyramine, 2-OG, AIBG, and ORM1– are elevated in cystitis.
Various elevated proliferative factors such as PD-ECGF, VEGF, NGF, EGF, HB-EGF, and anti-proliferative factor (APF) –the most promising biomarker– have also been found in IC. Regulated by APF, pro-inflammatory genes promote inflammatory cellular responses within the bladder. These mediators represent potential targets for therapeutic intervention.
Recently, more efforts have been focused in studying transcriptome profiles and urinary metabolites as disease biomarkers.
Most treatments are aimed at symptom control, including different phases: 1) behavioural therapy to change lifestyle, 2) prescription drugs, 3) neuromodulation therapy, ulcer cauterization and injections of Botox® into the bladder muscle, 4) immunosuppressant cyclosporine, and ultimately 5) surgery – escalating to avoid aggressive intervention at an early stage– in very rare and severe cases.
Although most patients improve with treatment, some do not respond to any IC/BPS therapy and need pain management. Moreover, IC/BPS symptoms can suffer recurrence even if the disease has been in remission for a long time.
Lines of treatment
Management of BPS must be individualized and empiric, with first level focused on patient education.
The second-line comprises pharmaceutical treatment, both oral –including amitriptyline, cimetidine, pentosan polysulphate and hydroxyzine–, and intravesical options –DMSO, heparin and lidocaine.
The third-line treatments cover endoscopic interventions such as hydrodistension and injection of triamcinolone, an intermediate acting synthetic glucocorticoid, while fourth-line recommendations ensue intravesical injection of botulinum A toxin or a trial of neurostimulation, and the fifth-line involves the use of oral cyclosporine A.
Current best practice and treatment of BPS is set out by three recent evidence-based published guidelines: the American Urology Association (AUA) Guidelines 2014; the Royal College of Obstetricians and Gynaecologists (RCOG) in conjunction with the British Society of Urogynaecologists (BSUG) Guidelines 2016; and the European Association of Urology (EAU) Guidelines updated in March 2017, which are proposing different types of conservative, medical therapy, and surgical treatment.
Due to a lack of evidence, the best practice in the management of patients with BPS is to adopt all the international guidelines in a summarized and personalized manner.
Regarding pharmacological agents, amitriptyline and nortriptyline are commonly recomeded by the EAU Guidelines. Pentosan polysulphate is associated with subjective improvement in symptoms, while azathioprine has shown efficacy in reducing both pain and symptoms. Cyclosporin A and methotrexate help with pain. Corticosteroids are not recommended. Intravesical treatments include local anaesthetic, hyaluronic acid or chondroitin sulphate and heparin. Endoscopic resection or electrocautery of Hunner’s lesions is the only surgical procedure with any effectiveness, and often relieves pain, but sometimes the lesions and the pain recur.
Novel Treatments and Future Research
Liposomes have been shown to enhance the penetration of both water-soluble and insoluble drugs, toxins, and oligonucleotides across the bladder epithelium. Liposomes have also been used as a delivery platform for the instillation of botulinum toxin in overactive bladder patients.
Empty liposomes composed of phingomyelin could counter mucosal inflammation and promote wound healing in patients suffering from IC. Based on the available evidence, the mechanism of action for empty liposomes in the bladder could involves a combination of a physical coating on the urothelium, and also a drug‐like action that promotes repair and regeneration of the bladder lining. Ongoing researches support the use of liposome as a promising therapy for the clinical treatment of IC/PBS patients.
However, more studies are still needed to understand the molecular mechanisms and pathology in order to diagnose and treat IC/BPS. In addition, there is a disconnection between IC/BPS treatment guidelines based on clinical trial data efficacy and effectiveness in real clinical practice. Thus, the optimal therapy must include the best evidence-based from clinical trials, but also patient experience from practice.Abbreviations
AIBG: alpha-IB glycoprotein
APF: anti-proliferative factor
AUA: American Urology Association
BPS: bladder pain syndrome
BCG: Bacille Calmette Guerin
BSUG: British Society of Urogynaecologists
CFS: chronic fatigue syndrome
CRP: C-reactive protein
CXCL10: C-X-C motif chemokine 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10)
CXCR3: C-X-C Motif Chemokine Receptor 3
DMSO: dimethyl sulphoxide
EAU: European Association of Urology
ESSIC: European Society for the Study of BPS
HB-EGF: heparin-binding epidermal growth factor-like growth factor
IBS: irritable bowel syndrome
IC: interstitial cystitis
IL-6 : interleukin 6
mRNA: messenger RNA
NGF: nerve growth factor
ORM1: gene that code Orosomucoid 1
PD-ECGF: platelet-derived endothelial cell growth factor
RCOG: Royal College of Obstetricians and Gynaecologists
TNFSF14: tumor necrosis factor superfamily member 14
UTI: urinary tract infection
VEGF: vascular endothelial growth factor
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