Immunomodulation—A Molecular Solution to Treating Patients with Severe Bladder Pain Syndrome?

Abstract

Background Patients with bladder pain syndrome experience debilitating pain and extreme frequency of urination. Numerous therapeutic approaches have been tested, but as the molecular basis of disease has remained unclear, specific therapies are not available. Objective Recently, a systematic gene deletion strategy identified interleukin-1 (IL-1) hyperactivation as a cause of severe cystitis in a murine model. Treatment with an IL-1 receptor antagonist (IL-1RA) restored health in genetically susceptible mice, linking IL-1–dependent inflammation to pain and pathology in the bladder mucosa. The study objective was to investigate whether IL-1RA treatment might be beneficial in patients with bladder pain syndrome. Design, setting, and participants Patients diagnosed with bladder pain syndrome were invited to participate and subjected to daily IL-1RA injections for 1 wk, followed by a treatment break. Patients with other urological disorders accompanied by pain were included as controls. Outcome measurements and statistical analysis When symptoms returned, treatment was resumed and responding patients were maintained on treatment long term, with individualized dosing regimens. Symptom scores were recorded and molecular effects were quantified by neuropeptide and gene expression analysis. DNA samples were subjected to exome genotyping. Results and limitations IL-1RA treatment reduced bladder pain and the frequency of urination in 13/17 patients ( p < 0.001). Substance P levels in urine were lowered, and responders returned to a more normal lifestyle. Neuroinflammatory-dependent and IL-1–dependent gene networks were inhibited, as well as regulators of innate immunity. Genotyping revealed disease-associated IL1R1, NLRP3 , and IL1RN DNA sequence variants in the responders. Controls did not benefit from IL-1RA treatment, except for one patent with cystitis cystica. Conclusions In this clinical study, IL-1RA treatment is proposed to reduce chronic bladder pain, immediately and in the long term. Despite the limited number of study patients, the potent acute effect and lasting symptom relief indicate that this therapeutic approach may be worth exploring in controlled clinical trials. Patient summary Treatment with an interleukin-1 (IL-1) receptor antagonist is proposed for treating bladder pain syndrome, as it can result in symptom relief and increase quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects.

Immunomodulation therapy offers new molecular strategies to treat UTI

“…This approach differs from the use of broad anti-inflammatory compounds, in that it seeks to correct specific innate immune defects in susceptible hosts. Potent therapeutic effects have been achieved in animal models, and patients with IC/BPS have responded favourably to off-label treatment with an IL-1RA 187 , but further studies are needed to understand the clinical potential of this approach. Controlled clinical trials are being initiated to improve understanding of the potential of IL-1RA treatment for ACY and important future target populations include patients with infections caused by antibiotic-resistant strains, in whom the need for new therapeutic options is immediately obvious.…”

“…The extent to which these successful treatment strategies in mice can be translated to human ACY needs to be investigated in controlled clinical studies; however, insights into the human relevance of innate immunomodulation therapy have been gained in patients with IC/BPS 187 . These patients experience severe and debilitating pain during bladder filling, resulting in extreme urgency and frequency 188 , 189 .…”

“…The IL-1β-dependent and NK1R-dependent pain response in the mouse ACY model suggested that IL-1RA therapy might be an option for this patient group. Patients with severe IC/BPS ( n = 17) were, therefore, offered off-label IL-1RA treatment 187 , and ~70% of the patients showed an initial treatment response, characterized by a reduction in pain and micturition frequency and an increased quality of life, quantified by O’Leary’s symptom score (7.2 versus 17.4) 187 . Clinical improvement was accompanied by a reduction in urine SP levels and gene expression analysis revealed considerable effects on neuroinflammatory and inflammatory gene sets, including IL-1, IL-6 and IL-8 signalling pathways, which were inhibited 187 .…”

“…Patients with severe IC/BPS ( n = 17) were, therefore, offered off-label IL-1RA treatment 187 , and ~70% of the patients showed an initial treatment response, characterized by a reduction in pain and micturition frequency and an increased quality of life, quantified by O’Leary’s symptom score (7.2 versus 17.4) 187 . Clinical improvement was accompanied by a reduction in urine SP levels and gene expression analysis revealed considerable effects on neuroinflammatory and inflammatory gene sets, including IL-1, IL-6 and IL-8 signalling pathways, which were inhibited 187 . After the initial treatment cycle, 13 of the patients chose to continue IL-1RA treatment and individual treatment protocols have proven efficient in the long term (>1 year) 187 .…”

“…Clinical improvement was accompanied by a reduction in urine SP levels and gene expression analysis revealed considerable effects on neuroinflammatory and inflammatory gene sets, including IL-1, IL-6 and IL-8 signalling pathways, which were inhibited 187 . After the initial treatment cycle, 13 of the patients chose to continue IL-1RA treatment and individual treatment protocols have proven efficient in the long term (>1 year) 187 .…”