Interstitial cystitis

Interstitial cystitis is a clinical syndrome, the main symptoms of which are considered to be chronic pelvic pain, frequent painful urination, imperative urges and nocturia (in the presence of sterile urine). In most patients, in the absence of Hunner's ulcer, which is characteristic of this disease, this is a diagnosis of exclusion.

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Epidemiology

Given the complexity and ambiguity of diagnostic criteria, epidemiological studies are extremely difficult. According to Oravisto, in Finland in 1975 the incidence of interstitial cystitis in women was 18.1 cases per 100,000; the combined incidence of men and women was 10.6 per 100,000. Severe interstitial cystitis was diagnosed in 10% of patients. In 1989, a population study in the United States found 43,500 patients with a confirmed diagnosis of interstitial cystitis. A little later, in 1990, Held diagnosed 36.6 cases of the disease per 100,000. In 1995, in the Netherlands, 8 to 16 cases of interstitial cystitis were found per 100,000 population. However, there are no data on its prevalence in our country.

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Causes interstitial cystitis

Risk factors for the development of interstitial cystitis include surgical interventions in gynecology, obstetrics, spastic colitis, irritable bowel syndrome, rheumatoid arthritis, bronchial asthma, allergic reactions to medications, autoimmune and some other diseases.

Thus, despite the diversity of theories of interstitial cystitis development (impaired urothelial cell permeability, autoimmune mechanisms, genetic predisposition, neurogenic and hormonal factors or exposure to toxic agents), its etiology and pathogenesis are unknown. In this regard, treatment of this category of patients is a complex task, and of the many drugs used in the treatment of the disease, none is 100% effective.

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Symptoms interstitial cystitis

The main symptoms of interstitial cystitis are pain in the pelvic area and frequent urination (up to a hundred times a day without incontinence) and persist at night, which leads to social maladjustment of patients: 60% of patients avoid sexual relations; the number of suicides among patients is twice as high as in the population.

Interstitial cystitis is one of the causes of chronic pelvic pain in women and chronic abacterial prostatitis or prostatodynia in men.

A multifactorial theory of bladder wall changes in patients with interstitial cystitis has been adopted, which includes changes in the surface of the urothelium and extracellular matrix, increased urothelium permeability, the influence of mast cells, and changes in the afferent innervation of the bladder wall (neuroimmune mechanism).

Forms

Ulcers are fissures, often covered with fibrin, penetrating into the lamina propria, but not deeper than the muscular layer. An inflammatory infiltrate consisting of lymphocytes and plasma cells occurs around the ulcer. Ulcerative lesions of the bladder in interstitial cystitis must be differentiated from radiation injuries, tuberculosis and tumors of the bladder and pelvic organs.

Only the presence of Hunner's ulcer of the bladder is considered an indication for endoscopic treatment (TUR, coagulation, transurethral laser resection).

When the capacity of the bladder decreases, accompanied by disturbances in the urodynamics of the upper urinary tract, various types of augmentation intestinal plastics or cystectomy with replacement plastic surgery of the bladder are performed.

The results of multicenter studies have proven that monotherapy cannot be used in the treatment of interstitial cystitis (painful bladder syndrome). Only complex therapy based on the individual characteristics of the patient, the use of drugs with proven effectiveness, affecting the known links of the pathogenesis of the disease can be successful. Thus, despite the variety of drugs used to treat interstitial cystitis, none of them can be considered completely effective.

Multicenter randomized placebo-controlled studies are needed to decide whether one or another treatment method is appropriate. And as Hanash and Pool said about interstitial cystitis back in 1969: "... the cause is unknown, the diagnosis is difficult, and the treatment is palliative, the effect is short-lived."

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Diagnostics interstitial cystitis

The main stages of diagnostics of interstitial cystitis: analysis of patient complaints (including various types of questionnaires - Pelvic Pain and Urgency/Frequence Patient Symptom Scale), examination data, cystoscopy (presence of Hunner's ulcer, glomerulations) and UDI; potassium test, exclusion of other diseases of the lower urinary tract, occurring with a similar clinical picture.

NIH/NIDDK criteria for the diagnosis of interstitial cystitis

Exclusion criteria	Positive factors	Inclusion Criteria
Age under 18 years; Bladder tumor; Stones of the ureter, bladder; Tuberculous cystitis; Bacterial cystitis; Post-radiation cystitis, Vaginitis; Genital tumors; Genital herpes; Diverticulum of the urethra; Frequency of urination less than 5 times per hour; Nocturia less than 2 times; Duration of the disease is less than 12 months	Pain in the bladder when it is full, which subsides during urination. Constant pain in the pelvic area, above the pubis, in the perineum, vagina, urethra. Cystometric capacity of the bladder is less than 350 ml, no detrusor instability. Glomerulations in cystoscopy	Presence of Hunner's ulcer in the bladder

According to the cystoscopic picture, two forms of interstitial cystitis are distinguished: ulcerative (development of Hunner's ulcer), observed in 6-20% of cases, non-ulcerative, which is detected much more often.

As stated above, one of the theories of interstitial cystitis development is considered to be damage to the glycosaminoglycan layer. The potassium test used in the diagnosis of this disease indicates the presence of increased permeability of the urothelium for potassium, which in turn leads to the occurrence of severe pain in the bladder when it is introduced. It should be noted that this test has low specificity, and a negative result does not exclude the presence of interstitial cystitis in the patient.

Methodology for conducting the potassium test

• Solution 1: 40 ml of sterile water. Within 5 minutes, the patient evaluates the pain and the presence of an imperative urge to urinate using a 5-point system.
• Solution 2: 40 ml of 10% potassium chloride in 100 ml of sterile water. Within 5 minutes, the patient evaluates the pain and the presence of an imperative urge to urinate using a 5-point system.

Correlation of a positive potassium test and the PUF-scale score during the potassium test

PUF-scale scores	Positive test result, %
10-14	75
15-19	79
>20	94

Due to the intermittent and progressive increase in signs of the disease, as well as the non-specificity of symptoms, which may be caused by other gynecological and urological diseases, diagnosing interstitial cystitis is quite difficult.

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Treatment interstitial cystitis

Principles of treatment of interstitial cystitis:

• restoration of the integrity of the urothelium;
• reduction of neurogenic activation;
• suppression of the cascade of allergic reactions.

Based on the mechanism of action, the main types of conservative treatment for interstitial cystitis are divided into three categories:

• drugs that directly or indirectly alter nervous function: narcotic or non-narcotic analgesics, antidepressants, antihistamines, anti-inflammatory drugs, anticholinergics, antispasmodics;
• cytodestructive methods that destroy umbrella cells of the bladder and lead to remission after their regeneration: hydrobougienage of the bladder, instillation of dimethyl sulfoxide, silver nitrate;
• cytoprotective methods that protect and restore the mucin layer in the bladder. These drugs include polysaccharides: sodium heparin, sodium pentosan polysulfate and, possibly, hyaluronic acid.

The European Association of Urology has developed levels of evidence and recommendations for the treatment of interstitial cystitis (painful bladder syndrome).

• Levels of evidence:
  • 1a - data from meta-analyses or randomized trials;
  • 1c - data from at least one randomized study;
  • 2a - one well-designed controlled study without randomization;
  • 2c - one well-organized study of another type;
  • 3 non-experimental research (comparative research, series of observations);
  • 4 - expert committees, expert opinions.
• Recommendation level:
• A - Clinical recommendations are based on high-quality research, including at least one randomized trial:
• B - clinical recommendations are based on studies without randomization;
• C - lack of applicable clinical studies of adequate quality.

Treatment of interstitial cystitis: use of antihistamines

Histamine is a substance released by mast cells and inducing the development of pain, vasodilation and hyperemia. It is generally accepted that mast cell infiltration and activation is one of the many links in the pathogenesis of interstitial cystitis. This theory served as the basis for the use of antihistamines in the treatment of interstitial cystitis.

Hydroxyzine is a tricyclic piperazine-histamine-1 receptor antagonist. T.S. Theoharides et al. were the first to report its efficacy at a dose of 25-75 mg per day in 37 of 40 patients with interstitial cystitis.

Cimetidine is an H2-receptor blocker. The clinical efficacy of cimetidine (400 mg twice daily) was proven in a double-blind, randomized, placebo-controlled prospective study in 34 patients with non-ulcer interstitial cystitis. A significant decrease in the severity of the clinical picture was obtained in the group of patients receiving treatment (from 19.7 to 11.3) compared with placebo (19.4 to 18.7). Pain above the pubis and nocturia are the symptoms that regressed in most patients.

It should be noted that no changes in the bladder mucosa were detected during biopsy before and after treatment with antihistamines, so the mechanism of action of these drugs remains unclear.

Treatment of interstitial cystitis: use of antidepressants

Amitriptyline is a tricyclic antidepressant that affects central and peripheral anticholinergic activity, has antihistamine, sedative effects and inhibits the reuptake of serotonin and norepinephrine.

In 1989, Nappo et al. first indicated the effectiveness of amitriptyline in patients with suprapubic pain and frequent urination. The safety and effectiveness of the drug for 4 months at a dose of 25-100 mg was proven in a double-blind, randomized, placebo-controlled prospective study. Pain and urgency of urination in the treatment group significantly decreased, bladder capacity increased, but insignificantly.

Nineteen months after the end of treatment, a good response to the drug was maintained. Amitriptyline has a pronounced analgesic effect at the recommended dose of 75 mg (25-100 mg). It is lower than the dose used to treat depression (150-300 mg). Regression of clinical symptoms develops quite quickly - 1-7 days after the start of taking the drug. The use of a dose over 100 mg is associated with the risk of sudden coronary death.

The glycosaminoglycan layer is a part of a healthy urothelial cell that prevents damage to the latter by various agents, including infectious ones. One of the hypotheses for the development of interstitial cystitis is damage to the glycosaminoglycan layer and the diffusion of damaging agents into the wall of the bladder.

Pentosan polysulfate sodium is a synthetic mucopolysaccharide produced in the form for oral administration. Its action consists in correction of defects of the glycosaminoglycan layer. It is used at 150-200 mg twice a day. In placebo-controlled studies, a decrease in urination, a decrease in its urgency, but not nocturia, was noted. Nickel et al., using various doses of the drug, proved that their increase does not lead to a more significant improvement in the patient's quality of life. The duration of use of the drug is of certain importance. The appointment of pentosan polysulfate sodium is more appropriate for non-ulcer forms of interstitial cystitis.

Side effects of the drug at a dose of 100 mg three times a day are observed quite rarely (less than 4% of patients). Among them are reversible alopecia, diarrhea, nausea and rash. Bleeding occurs very rarely. Given that the drug in vitro increases the proliferation of MCF-7 breast cancer cells, it should be prescribed with caution to patients with a high risk of developing this tumor and women of premenopausal age.

Other oral medications that have ever been used to treat interstitial cystitis include nifedipine, misoprostol, methotrexate, montelukast, prednisolone, and cyclosporine. However, the groups of patients taking the medications are relatively small (from 9 to 37 patients), and the effectiveness of these drugs has not been statistically proven.

According to L. Parsons (2003), treatment of interstitial cystitis using the following drugs can be successful in 90% of patients:

• pentosan sodium polysulfate (orally) 300-900 mg/day or sodium heparin (intravesically) 40 thousand IU in 8 ml of 1% lidocaine and 3 ml of isotonic sodium chloride solution;
• hydroxyzine 25 mg at night (50-100 mg in spring and autumn);
• amitriptyline 25 mg at night (50 mg every 4-8 weeks) or fluoxetine 10-20 mg/day.

Treatment of interstitial cystitis: sodium heparin

Considering that damage to the glycosaminoglycan layer is one of the factors in the development of interstitial cystitis, sodium heparin is used as an analogue of the mucopolysaccharide layer. In addition, it has an anti-inflammatory effect, inhibits angiogenesis and proliferation of fibroblasts and smooth muscles. Parsons et al. indicate the effectiveness of administering 10 thousand IU of sodium heparin 3 times a week for 3 months in 56% of patients; remission persisted for 6-12 months (in 50% of patients).

The use of sodium heparin after a course of intravesical administration of dimethyl sulfoxide is considered an effective treatment method.

Good results were obtained with intravesical administration of sodium heparin with hydrocortisone in combination with oxybutynin and tolterodine. The effectiveness of the method was 73%.

Treatment of interstitial cystitis: hyaluronic acid

Hyaluronic acid is a component of the glycosaminoglycan layer, which is found in high concentrations in the subepithelial layer of the bladder wall and is designed to protect its wall from irritating components of urine. In addition, hyaluronic acid binds free radicals and acts as an immunomodulator.

Morales et al. investigated the efficacy of intravesical administration of hyaluronic acid (40 mg once a week for 4 weeks). Improvement was defined as a reduction in symptom severity by more than 50%. The efficacy of use increased from 56% after administration for 4 weeks to 71% after use for 12 weeks. The effect was maintained for 20 weeks. No signs of toxicity of the drug were detected.

Treatment of interstitial cystitis: dimethyl sulfoxide

The effect of the drug is based on increasing membrane permeability, anti-inflammatory and analgesic action. In addition, it promotes collagen dissolution, muscle wall relaxation, and the release of histamine by mast cells.

Three studies have been conducted demonstrating a reduction in the severity of symptoms in 50-70% of patients using dimethyl sulfoxide at a 50% concentration. Perez Marrero et al. in a placebo-controlled study in 33 patients confirmed the effectiveness (in 93% of cases) of intravesical administration of dimethyl sulfoxide compared with placebo (35%). The data were confirmed by UDI, questionnaires, and urination diaries. However, after four courses of treatment, the recurrence rate of the disease was 59%.

Treatment of interstitial cystitis: use of BCG therapy

Pathogenetic rationale for the use of the BCG vaccine for bladder cancer immunotherapy includes immune dysregulation with possible development of an imbalance between T2 and T2 helpers. Intravesical administration of the vaccine is a method of immunotherapy for superficial bladder cancer.

The data on the effectiveness of BCG therapy are very contradictory - from 21 to 60%. The ICCTG study indicates that it is inappropriate to treat interstitial cystitis with the use of the BCG vaccine for bladder cancer immunotherapy with moderate and severe clinical symptoms.

A comparative study of the use of dimethyl sulfoxide and BCG vaccines for the immunotherapy of bladder cancer showed that no advantages of BCG therapy were found.

Its action is based on ischemic necrosis of sensory nerve endings in the bladder wall, an increase in the concentration of heparin-bound growth factor and a change in microvascularization, but at present the level of evidence for this treatment method is 3C.

It is not recommended to perform sacral neuromodulation outside specialized departments (level of evidence - 3B).