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

Wullt, Björn LU ; Butler, Daniel S.C. LU ; Ambite, Ines LU orcid ; Kinsolving, Julia ; Krintel, Christian LU and Svanborg, Catharina LU (2021) In European Urology Open Science 31. p.49-58
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... (More)

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. Take Home Message: Interleukin-1 (IL-1) receptor antagonist immunotherapy is proposed as a new approach to treating bladder pain syndrome, a debilitating disorder. Treated patients experienced symptom relief and increased quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bladder pain syndrome, Immunotherapy, Interleukin-1 receptor antagonist, Interstitial cystitis
in
European Urology Open Science
volume
31
pages
10 pages
publisher
Elsevier
external identifiers
  • scopus:85111978833
  • pmid:34467240
ISSN
2666-1691
DOI
10.1016/j.euros.2021.07.003
language
English
LU publication?
yes
id
d4589161-d6a3-4915-bd5b-165f6ce01c0a
date added to LUP
2021-12-28 13:16:10
date last changed
2024-06-15 23:27:59
@article{d4589161-d6a3-4915-bd5b-165f6ce01c0a,
  abstract     = {{<p>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 &lt; 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. Take Home Message: Interleukin-1 (IL-1) receptor antagonist immunotherapy is proposed as a new approach to treating bladder pain syndrome, a debilitating disorder. Treated patients experienced symptom relief and increased quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects.</p>}},
  author       = {{Wullt, Björn and Butler, Daniel S.C. and Ambite, Ines and Kinsolving, Julia and Krintel, Christian and Svanborg, Catharina}},
  issn         = {{2666-1691}},
  keywords     = {{Bladder pain syndrome; Immunotherapy; Interleukin-1 receptor antagonist; Interstitial cystitis}},
  language     = {{eng}},
  pages        = {{49--58}},
  publisher    = {{Elsevier}},
  series       = {{European Urology Open Science}},
  title        = {{Immunomodulation—A Molecular Solution to Treating Patients with Severe Bladder Pain Syndrome?}},
  url          = {{http://dx.doi.org/10.1016/j.euros.2021.07.003}},
  doi          = {{10.1016/j.euros.2021.07.003}},
  volume       = {{31}},
  year         = {{2021}},
}