Is there an effective therapy of interstitial cystitis/bladder pain syndrome?

KEYWORDS:

• Interstitial cystitis
• bladder painful syndrome
• Hunner’s lesion
• pentosan polysulfate sodium
• dimethyl sulfoxide
• cyclosporine A
• neuromodulation
• botulinum toxin

1. Introduction

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood, highly debilitating chronic condition negatively affecting the patient’s quality of life (QoL), especially women’s [1]. It represents a heterogeneous spectrum of disorders [2] and is characterized by a persistent or recurrent pain or discomfort perceived in the retropubic area, accompanied by at least one other symptom (i.e. pain worsening with bladder filling and daytime or nighttime urinary frequency), in the absence of a distinctively identifiable cause or proven urinary tract infection (UTI) [3,4]. Practically, IC/BPS is a diagnosis of exclusion and requires the presence of pain, pressure or discomfort in addition to at least one urinary symptom without the presence of UTI, bladder or renal calculi, cancer or other bladder or urethral pathology [3,5]. Although highly prevalent, its definition and management remain debatable since there is still a lack of consensus worldwide on how to define the condition, the nomenclature to use, and how to optimally treat patients, reflecting the considerable variation in management, and the divergent recommendations in guidelines [5]. Several etiologies have been postulated, while an abnormal immune response is thought to be involved in IC/BPS related symptoms [6]. Hunner’s lesion is a typical cystoscopic finding in IC/BPS patients, with a prevalence of 10–50% of cases [6]. At present, there are two major subtypes of IC/BPS: with or without Hunner’s lesion, which are also known as ulcerative or non-ulcerative IC/BPS, respectively [3,6]. Ulcerative IC/BPS is thought to represent a different disease process, requiring different management strategies, and there is a debate about whether this should now be completely separated from IC/BPS [5]. Principles of management of patients with IC/BPS are to encourage realistic patient expectations, improve symptoms and QoL as well as suggest safe and effective treatment options; moreover, the positive balance between potential benefits and adverse events should be examined.

Herein, taking into consideration the aforementioned ‘criteria’, we will present data regarding the most effective treatment of IC/BPS.

2. Pathophysiology

IC/BPS is an enigmatic clinical entity, which is not only difficult to diagnose due to the lack of certain diagnostic criteria but also challenging to treat [7]. It frequently precedes, co-exists or follows other functional somatic syndromes and might be exacerbated by stress [2]. Several causes have been proposed for the IC/BPS pathogenesis: from stress and UTIs in childhood and adolescence to more complex causes, such as ten-fold increased mast-cell counts in the bladder tissue and their secreted mediators [2,8]. Cystoscopy and biopsy findings are consistent with defects in the urothelial glycosaminoglycan (GAG) layer due to imbalances in the damage-repair process of the urothelium. This defective mechanism results in suburothelial nerve filaments exposure to irritative and harmful urine components [2,8]. Tight-junction proteins down-regulation, increased urothelial permeability, microvascular alterations along with lower mature to total vessels ratio are possible pathogenetic processes [2,6]. Involvement of neurogenic inflammation as the trigger to a cascade of symptoms in IC/BPS due to bladder afferent nerves activation has been confirmed [9], while recently has been postulated that the sensitization of the central nervous system and an abnormal immune response may also be involved in the pathogenesis of IC/BPS [6].

3. Management options

Since the complete pathophysiology of IC/BPS is not understood, there is no established diagnostic workup. It is widely accepted that IC/BPS diagnosis can be clinical, based on a thorough history, physical examination and laboratory tests, however, invasive diagnostics such as cystoscopy and hydrodistention are not adopted procedures by all international guidelines and are considered as optional. The aforementioned lack of consensus even in diagnostic strategy results in a variety of treatment approaches.

Principles of management include the improvement of the QoL and the encouragement of realistic patient expectations. The optimal management should involve – but not be limited to – lifestyle modifications, multimodal behavioral, physical, and psychological techniques and should proceed in a step-wise manner, starting with the most conservative [10].

Currently, the philosophy for the management of IC/BPS is based on a biopsychosocial model, which is a holistic approach with the patients’ active involvement [8]. Multiple treatment modalities may be necessary, and various treatments have been suggested; however, no one has demonstrated adequate efficacy in relieving symptoms [11]. According to both European (EAU) [2] and American Urological Associations (AUA) [3], the IC/BPS management strategy should include psychology, physiotherapy, drugs and more invasive interventions [2,3]. Traditionally, for the treatment of IC/BPS, conservative therapies are offered initially and more invasive and/or surgical therapies follow [12].

According to the AUA guidelines, standard treatments are: behavioral therapy, pain control, oral, or intravesical medication, as well as bladder hydrodistention and cystoscopic treatment of Hunner’s lesions if found [3]. However, they often fail and are characterized by limited efficacy and a rather short duration of symptom’s improvement. Botulinum toxin (BTX) as the sole treatment or in combination with hydrodistention, and cyclosporine, are therapeutic options in case of other treatments fail to improve symptoms and QoL. Urinary diversion (with or without cystectomy) and substitution cystoplasty are performed only in the very rare instance when a small, fibrotic bladder has been confirmed and all other treatments failed [3].

The EAU guidelines strongly recommend multimodal behavioral, physical, and psychological techniques along with oral, such as amitriptyline and pentosan polysulfate sodium (PPS) (the latter potentially in combination with intravesical instillation) or invasive treatments of IC/BPS [2]. Suburothelial BTX plus hydrodistention or ablative organ surgery should be undertaken only if other therapies fail and only by experienced surgeons, while intravesical or trigonal BTX injections are strongly recommended if intravesical instillation therapies fails [2,8].

Discrepancies exist further in approved-for-use formulations in USA and Europe, since the only US Food and Drug Administration (FDA)-approved treatment options include PPS orally administered and intravesical dimethyl sulfoxide (DMSO), while in Europe there are several formulations of chondroitin sulfate (CS) available commercially for IC/BPS intravesical therapy [13].

4. Expert opinion

Although IC/BPS is a well-known chronic debilitating condition, it is still a pathophysiological enigma and its definitive multifunctional etiopathogenesis is not yet clear. IC/BPS was originally considered to be a bladder disease; however, it has now been recognized as a chronic polymorphic syndrome with ‘episodic’ nature [3,8]. In order to overcome this unique multifactorial nature that is further influenced by each patient’s personality, a recent phenotypical classification (UPOINT) [14] and its further improvement (INPUT) [15] has been proposed to better guide research and individualized medicine.

Patients should be realistically counseled regarding the chronic and episodic nature of IC/BPS and the need for staged therapy depends on the severity or relapse of symptoms. Lifestyle modifications, such as dietary changes, timed voiding or physiotherapy courses are suggested initial options that can be combined with oral or intravesical therapies. Regarding the former, amitriptyline suggests a generally accepted oral regimen, with proven efficacy in several RCTs. PPS is an orally administered agent, US-FDA approved for IC/BPS. Although with promising initial results, recent data question its efficacy in IC/BPS treatment [16]. Immunosuppressive agents, such as cyclosporine A (CyA), are underway for the IC/BPS treatment. CyA’s use is further supported by measuring urine and blood ‘biomarkers’ during treatment [16]. Although promising with initial better results than PPS and recommended by the AUA guidelines, it is not currently approved by the US-FDA. As far as the latter is concerned, DMSO has shown proven efficacy in two randomized trials and is recommended by the AUA but not the EAU guidelines. PPS as intravesically instilled therapy alone or in combination with oral PPS is recommended by the AUA guidelines, while intravesical alkalinized lignocaine or lidocaine/sodium bicarbonate are other agents with promising results. If the aforementioned therapeutic options fail, bladder hydrodistention with potential Hunner’s lesion fulguration, are reliable IC/BPS treatment options (although there is no technique standardization for hydrodistention). In the field of intervention, the use of BTX for bladder wall injections seems a very attractive option with proven efficacy and is recommended by the EAU and AUA guidelines when other treatments fail, along with sacral neuromodulation (SNM). What needs to be further clarified is when the swift to more invasive procedures should be proposed.

Unfortunately, none of the existing medications has been established as strongly effective for the management of IC/BPS. Therefore, optimal treatment is expected to be the result of accurate diagnosis and tailor-made individualized phenotype-directed therapies. We believe that this classification is the best approach to treat IC/BPS patients, rather than the usual ‘one size fits all’ paradigm [8]. Tailor-made individualized phenotype-directed multimodal treatment plan should be preferred than traditional unsuccessful therapies, especially for refractory patients [14,15], with a combination of lifestyle modifications and oral pharmaceutical agents initially. Intravesical instillations or more interventional procedures should be reserved if initial treatments fail. Relevant basic research on clarifying the exact pathogenic mechanisms and development of specific biomarkers, as well as clinical trials with proper design including immunomodulating are warranted, since a high level of evidence studies are still missing.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.