Interstitial cystitis

Interstitial cystitis is a clinical syndrome whose main symptoms are chronic pelvic pain, frequent urination, urgency and nocturia (with sterile urine). In most patients, in the absence of a characteristic Gunner ulcer, this is an exception diagnosis.

[1], [2], [3], [4]

Epidemiology

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

[5], [6], [7], [8], [9], [10]

Causes of the interstitial cystitis

The operative interventions in gynecology surgery, obstetrics, spastic colitis, irritable bowel syndrome, rheumatoid arthritis, bronchial asthma, allergic reactions to medications, autoimmune and some other diseases are among the risk factors for the development of interstitial cystitis.

Thus, despite the variety of theories of the development of interstitial cystitis (impairment of urothelial cell permeability, autoimmune mechanisms, genetically predisposed, 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 difficult task, and of the many drugs used in the treatment of the disease, none is 100% effective.

[11], [12], [13], [14]

Symptoms of the interstitial cystitis

The main symptoms of interstitial cystitis are pain in the pelvic region and increased urination (up to 100 times a day without incontinence) persist at night, which leads to social maladaptation of patients: 60% of patients avoid sexual relations; the number of suicides among patients is twice higher than 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 changes in the wall of the bladder in patients with interstitial cystitis has been adopted. These include changes in the surface of the urothelium and the extracellular matrix, an increase in the permeability of the urothelium, the influence of mast cells and a change in the afferent innervation of the bladder wall (neuroimmune mechanism).

Forms

Ulcers are cracks, often covered with fibrin penetrating the lamina propria, but not deeper than the muscle layer. Around the ulcer there is an inflammatory infiltrate, consisting of lymphocytes and plasma cells. Ulcerative lesions of the bladder with interstitial cystitis must be differentiated with radiation injuries, tuberculosis and tumors of the bladder and pelvic organs.

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

With a decrease in the capacity of the bladder, accompanied by violations of urodynamics of the upper urinary tract, perform various types of augmentative intestinal plastics or cystectomy with replacement bladder plastic.

The results of multicenter studies have shown that monotherapy can not be used in the treatment of interstitial cystitis (painful bladder syndrome). Successful can be 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. Thus, despite the variety of drugs used to treat interstitial cystitis, none of them can be considered completely effective.

It is necessary to conduct multicenter randomized placebo-controlled studies to determine the appropriateness of using a particular treatment method. And as they said back in 1969, Hanash and Pool about interstitial cystitis: "... The cause is unknown, the diagnosis is difficult, and the treatment is palliative, the effect is short-lived."

[15], [16], [17], [18]

Diagnostics of the interstitial cystitis

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

NIH / NIDDK criteria for diagnosis of interstitial cystitis

Exclusion criteria	Positive factors	Inclusion Criteria
The age is under 18 years; Bladder tumor; Stones of the ureter, bladder; Tuberculous cystitis; Bacterial cystitis; Post-radial cystitis, Vaginitis; Genital warts; 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 filled, it stops when you urinate. Constant pain in the projection of the small pelvis, above the bosom, in the perineum, vagina, urethra. Cystometric capacity of the bladder is less than 350 ml, lack of instability detrusora. Glomeruli in cystoscopy	The presence of Hunner's ulcer in the bladder

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

As mentioned above, one of the theories of the development of interstitial cystitis is considered to be affected by the glycosaminoglycan layer. Used in the diagnosis of this disease potassium test indicates the presence of increased permeability of urothelium for potassium, which. In turn, leads to the emergence of severe pain in the bladder when it is injected. It should be noted that this test has low specificity, and a negative result does not exclude the patient having an interstitial cystitis.

Method of conducting a 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 on 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 on a 5-point system.

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

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

In connection with the intermittent and progressive increase in the signs of the disease, as well as the nonspecificity of the symptoms that can be caused by other gynecological and urological diseases, it is quite difficult to diagnose interstitial cystitis.

[19], [20], [21], [22], [23]

Treatment of the 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.

According to the mechanism of action, the main types of conservative treatment of interstitial cystitis are divided into three categories:

• drugs that directly or indirectly alter the 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: hydroblocking of the bladder, installation of dimethylsulfoxide, silver nitrate;
• cytoprotective methods, protecting and restoring the layer of mucin in the bladder. These drugs include polysaccharides: sodium heparin, pentosan sodium polysulphate and, possibly, hyaluronic acid.

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

• Levels of Evidence:
  • 1a - meta-analysis or randomized trials;
  • 1c - data from at least one randomized trial;
  • 2a - one well-organized controlled trial without randomisation;
  • 2c - one well-organized study of another type;
  • 3 non-experimental study (comparative study, series of observations);
  • 4 - committees of experts, expert opinions.
• Degree of recommendations:
• A - Clinical recommendations are based on high-quality studies, including at least one randomized trial:
• B - Clinical recommendations are based on studies without randomization;
• C - absence of applicable clinical trials of proper 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 considered that infiltration by mast cells and their activation is one of the numerous links in the pathogenesis of the development of interstitial cystitis. This theory also served as the basis for the use of antihistamines in the treatment of interstitial cystitis.

Hydroxyzine is an antagonist of the tricyclic piperazine-histamine-1 receptor. T.S. Theoharides et al. First pointed out the effectiveness of its use in a dose of 25-75 mg per day in 37 of 40 patients with interstitial cystitis.

Cimetidine is a blocker of H2 receptors. The clinical efficacy of cimetidine (400 mg twice daily) was demonstrated in a double-blind, randomized, placebo-controlled prospective study in 34 patients with non-ulcerative form of interstitial cystitis. A significant decrease in the severity of the clinical picture in the group of patients treated (from 19.7 to 11.3) compared with placebo (19.4 to 18.7) was obtained. Pain over the bosom and nocturia are symptoms that regression occurred in most patients.

It should be noted that during the biopsy before and after treatment with antihistamines, there was no change in the mucous membrane of the bladder, 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, which has an antihistaminic, sedative effect and inhibits the reuptake of serotonin and norepinephrine.

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

After 19 months after the end of treatment, a good response to the use of the drug persisted. Amitriptyline has a pronounced analgesic effect in the recommended dose of 75 mg (25-100 mg). It is lower than the dose used to treat depression (150-300 mg). The regression of clinical symptoms develops rather quickly - 1-7 days after the start of the drug. The use of a dose of more than 100 mg is associated with a risk of sudden coronary death.

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

Pentosan sodium polysulphate is a synthetic mucopolysaccharide, available in the form for ingestion. Its action consists in correction of defects of the glycosaminoglaconic layer. Apply 150-200 mg twice a day. In placebo-controlled studies, there was a decrease in urination, a decrease in urgency, but no nocturia. Nickel et al., Using different doses of the drug, proved that their increase does not lead to a more significant improvement in the quality of life of the patient. A certain value has the duration of the drug. The administration of pentosan sodium polysulphate is more appropriate for non-ulcerative 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, we can note reversible alopecia, diarrhea, nausea and rash. Very rarely there is bleeding. Given that the drug in vitro enhances the proliferation of breast cancer cells MCF-7, it should be used with caution in patients at high risk of developing this tumor and women at pre-menopausal age.

Other oral medications that have ever been used in the treatment of interstitial cystitis include nifedipine, misoprostol, methotrexate, montelukast, prednisolone, cyclosporine. However, groups of patients taking drugs 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 (inside) 300-900 mg / day or heparin sodium (intravesical) 40,000 IU in 8 ml of 1% lidocaine and 3 ml isotonic sodium chloride solution;
• hydroxyzine at 25 mg per night (50-100 mg each in spring and autumn);
• amitriptyline at 25 mg per night (50 mg every 4-8 weeks) or fluoxetine 10-20 mg / day.

Treatment of interstitial cystitis: heparin sodium

Given that the damage to the glycosaminoglycan layer is one of the factors of the development of interstitial cystitis, sodium heparin is used as an analog of the mucopolysaccharide layer. In addition, it has an anti-inflammatory effect, inhibits angiogenesis and proliferation of fibroblasts and smooth muscle. Parsons et al. Indicate the effectiveness of 10,000 IU of sodium heparin 3 times per week for 3 months in 56% of patients; remission persisted for 6-12 months (in 50% of patients).

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

Good results were obtained with intravesical injection 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 contained in a high concentration in the subepithelial layer of the bladder wall and designed to protect its wall from irritating urine components. In addition, hyaluronic acid binds free radicals and acts as an immunomodulator.

Morales et al. The effectiveness of intravesical administration of hyaluronic acid (once a week for 40 mg for 4 weeks) was examined. Improvement was defined as a decrease in the severity of symptoms by more than 50%. Efficacy of use increased from 56% after administration for 4 weeks to 71% after application for 12 weeks. The effect lasted for 20 weeks. No evidence of toxicity was found.

Treatment of interstitial cystitis: dimethylsulfoxide

The effect of the drug is based on increased permeability of membranes, anti-inflammatory and analgesic action. In addition, it promotes dissociation of collagen, relaxation of the muscular wall, release of histamine by mast cells.

Three studies have shown a decrease in the severity of symptoms in 50-70% of patients using dimethylsulfoxide in 50% concentration. Perez Marrero et al. In a placebo-controlled study, 33 patients confirmed the efficacy (in 93% of cases) of intravesical administration of dimethylsulfoxide compared with placebo (35%). Data confirmed by UDI, questionnaires, diaries of urination. However, after four courses of treatment, the recurrence rate was 59%.

Treatment of interstitial cystitis: use of BCG therapy

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

Data on the effectiveness of BCG therapy are very controversial - from 21 to 60%. The ICCTG study indicates that treating interstitial cystitis with the use of a vaccine for the immunotherapy of bladder cancer BCG with mild and severe clinical symptoms is impractical.

In a comparative study of the use of dimethyl sulfoxide and vaccines for immunotherapy of BCG cancer, it has been shown that BCG therapy has not been shown to be beneficial.

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

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