The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Susanne M. Benseler - One of the best experts on this subject based on the ideXlab platform.

  • early detection of sensorineural hearing loss in Muckle Wells Syndrome
    Pediatric Rheumatology, 2015
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Stefan K. Plontke, Norbert Deschner, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Christiane Koitschev, Susanne M. Benseler
    Abstract:

    Muckle-Wells-Syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5–4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response.

  • il 1 inhibition in Muckle Wells Syndrome withdrawal resulting in rapid deterioration of hearing loss
    Pediatric Rheumatology, 2015
    Co-Authors: Sandra Hansmann, Assen Koitschev, K Ambjoernsen, Susanne M. Benseler
    Abstract:

    Muckle-Wells Syndrome (MWS), a phenotype within the spectrum of cryopyrine-associated periodic Syndrome (CAPS) is characterized by excessive IL-1 release resulting in chronic systemic and organ-specific inflammation including sensorineural hearing loss. During continuous anti-IL-1-therapy clinical symptoms are controlled and hearing loss remains stable. Limited data exists about discontinuation of IL-1-inhibition during the course of disease.

  • challenges in diagnosing Muckle Wells Syndrome identifying two distinct phenotypes
    Arthritis Care and Research, 2014
    Co-Authors: Samuel Dembi Samba, Pascal N. Tyrrell, Norbert Deschner, Isabelle Marie, Isabelle Konepaut, Susanne M. Benseler
    Abstract:

    Objective The diagnosis of Muckle-Wells Syndrome (MWS) remains challenging due to the clinical heterogeneity and lack of diagnostic criteria. The aims of this study were to describe key elements of the diagnostic evaluation process in MWS and compare identified variables between patients diagnosed in childhood and adulthood. Methods A cohort study of consecutive patients with a clinical and genetic diagnosis of MWS was conducted at 2 reference centers for autoinflammatory diseases. Demographic information, clinical presentation, access to care, and preclinical evaluation variables were captured. Presenting symptoms were compared between groups of patients diagnosed in childhood and adulthood. Prediction analysis explored variables associated with late diagnosis. Correspondence analysis identified clinical phenotypes. Results A total of 34 MWS patients were included (16 males, 18 females) and median age at diagnosis was 31.5 years (range 0.5–75 years). Patients diagnosed during childhood reported musculoskeletal symptoms (62%), rash (62%), fever (54%), and abdominal pain (31%). Those diagnosed as adults described musculoskeletal symptoms (86%), rash (67%), hearing loss (52%), and fatigue (29%). Hearing loss was associated with late diagnosis, while access-to-care variables were not predictive. Correspondence analysis identified distinct clinical phenotypes as follows: an “inflammatory phenotype” (most commonly seen in patients diagnosed in childhood and characterized by relapsing fever and abdominal pain), an intermediate phenotype, and an “organ-disease” phenotype in patients diagnosed during adulthood and characterized by fatigue and hearing loss. Conclusion Distinct clinical phenotypes were identified in patients with MWS. These are closely related to age at diagnosis. The presence of these phenotypes has to be considered when developing diagnostic criteria for MWS.

  • hearing loss in Muckle Wells Syndrome
    Arthritis & Rheumatism, 2013
    Co-Authors: Assen Koitschev, Stefan K. Plontke, Sandra Hansmann, Katharina Ummenhofer, Christiane Koitschev, Ina Koetter, Eva Angermair, Susanne M. Benseler
    Abstract:

    Objective Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin-1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes. Methods A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype-specific risk of progression of hearing loss was determined. Results A total of 33 patients ages 3–75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss. Conclusion Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions.

  • delayed diagnosis of Muckle Wells Syndrome analysis of influencing factors
    Pediatric Rheumatology, 2012
    Co-Authors: Jasmin B Kuemmerledeschner, Sandra Hansmann, Samuel Dembi Samba, Isabelle Marie, Katharina Gramlich, Isabelle Konepaut, Theodoros Xenitidis, Susanne M. Benseler
    Abstract:

    Purpose Muckle-Wells Syndrome (MWS) is a rare inherited autoinflammatory disease. Patients may present with fever, rash, arthralgia, or conjunctivitis. Effective treatment of MWS has become available with the advance of IL-1 inhibition preventing disease sequalae of sensorineural deafness and amyloidosis. Therefore, early diagnosis of MWS is crucial to prevent -organ damage. The aim of this study was to identify key factors contributing to a delay in diagnosis of MWS.

Peter Lohse - One of the best experts on this subject based on the ideXlab platform.

  • early detection of sensorineural hearing loss in Muckle Wells Syndrome
    Pediatric Rheumatology, 2015
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Stefan K. Plontke, Norbert Deschner, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Christiane Koitschev, Susanne M. Benseler
    Abstract:

    Muckle-Wells-Syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5–4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response.

  • treatment of Muckle Wells Syndrome analysis of two il 1 blocking regimens
    Arthritis Research & Therapy, 2013
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Helmut Wittkowski, Christoph Deuter
    Abstract:

    Objectives: Muckle-Wells Syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1b monoclonal antibody, can abolish excess IL-1b. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumabtreated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

  • nlrp3 e311k mutation in a large family with Muckle Wells Syndrome description of a heterogeneous phenotype and response to treatment
    Arthritis Research & Therapy, 2011
    Co-Authors: Peter Lohse, Katharina Ummenhofer, Ina Koetter, Fabian Reess, Anja Bialkowski, Nicolai Tzaribachev, Guenther E Dannecker, Silvia Koch, Susanne M. Benseler
    Abstract:

    Introduction: Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. Methods: A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. Results: All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/ E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-a, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. Conclusions: The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

  • nlrp3 e311k mutation in a large family with Muckle Wells Syndrome description of a heterogeneous phenotype and response to treatment
    Arthritis Research & Therapy, 2011
    Co-Authors: Jasmin B Kuemmerledeschner, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Anja Bialkowski, Nicolai Tzaribachev, Guenther E Dannecker, Silvia Koch, Susanne M. Benseler
    Abstract:

    Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

  • efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle Wells Syndrome
    Arthritis & Rheumatism, 2011
    Co-Authors: Pascal N. Tyrrell, Peter Lohse, Ina Koetter, Helmut Wittkowski, Anja Bialkowski, Nicolai Tzaribachev, Assen Koitchev, Christoph Deuter, Dirk Foell
    Abstract:

    Objective Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. Methods A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. Results A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5–14 months). The median followup was 11 months (range 5–14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. Conclusion Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

Assen Koitschev - One of the best experts on this subject based on the ideXlab platform.

  • early detection of sensorineural hearing loss in Muckle Wells Syndrome
    Pediatric Rheumatology, 2015
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Stefan K. Plontke, Norbert Deschner, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Christiane Koitschev, Susanne M. Benseler
    Abstract:

    Muckle-Wells-Syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5–4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response.

  • il 1 inhibition in Muckle Wells Syndrome withdrawal resulting in rapid deterioration of hearing loss
    Pediatric Rheumatology, 2015
    Co-Authors: Sandra Hansmann, Assen Koitschev, K Ambjoernsen, Susanne M. Benseler
    Abstract:

    Muckle-Wells Syndrome (MWS), a phenotype within the spectrum of cryopyrine-associated periodic Syndrome (CAPS) is characterized by excessive IL-1 release resulting in chronic systemic and organ-specific inflammation including sensorineural hearing loss. During continuous anti-IL-1-therapy clinical symptoms are controlled and hearing loss remains stable. Limited data exists about discontinuation of IL-1-inhibition during the course of disease.

  • treatment of Muckle Wells Syndrome analysis of two il 1 blocking regimens
    Arthritis Research & Therapy, 2013
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Helmut Wittkowski, Christoph Deuter
    Abstract:

    Objectives: Muckle-Wells Syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1b monoclonal antibody, can abolish excess IL-1b. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumabtreated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

  • hearing loss in Muckle Wells Syndrome
    Arthritis & Rheumatism, 2013
    Co-Authors: Assen Koitschev, Stefan K. Plontke, Sandra Hansmann, Katharina Ummenhofer, Christiane Koitschev, Ina Koetter, Eva Angermair, Susanne M. Benseler
    Abstract:

    Objective Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin-1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes. Methods A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype-specific risk of progression of hearing loss was determined. Results A total of 33 patients ages 3–75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss. Conclusion Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions.

  • Progressive familial hearing loss in Muckle-Wells Syndrome
    Acta oto-laryngologica, 2012
    Co-Authors: Assen Koitschev, Stefan K. Plontke, Sandra Hansmann, Christiane Koitschev, Susanne M. Benseler, Katharina Gramlich, Ina Koetter, Jasmin B. Kuemmerle-deschner
    Abstract:

    Abstract Conclusion: The age-dependent disease progression requires accelerating diagnosis of Muckle-Wells Syndrome (MWS) in order to start treatment as early as possible. The most frequent, but not obligate symptoms are familial fatigue, hearing loss, and arthralgia. The design of further clinical trials should focus on hearing in order to document the long-term effect of anti-interleukin (IL)-1 drugs on hearing preservation. Objectives: This paper describes the otologic features of a genetically defined Syndrome causing progressive hearing loss by cochlear degeneration. This is the first study reporting the pretreatment otologic presentation of a selected population with familial MWS. Methods: A single-center cohort was examined by audiologic and neurotologic methods including pure tone audiograms, vestibular testing, and tinnitus questionnaire. The audiograms of members of the same family were compared to describe the family-specific risk of hearing loss progression. Results: Nineteen patients (aged 3–...

Ina Koetter - One of the best experts on this subject based on the ideXlab platform.

  • treatment of Muckle Wells Syndrome analysis of two il 1 blocking regimens
    Arthritis Research & Therapy, 2013
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Helmut Wittkowski, Christoph Deuter
    Abstract:

    Objectives: Muckle-Wells Syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1b monoclonal antibody, can abolish excess IL-1b. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumabtreated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

  • hearing loss in Muckle Wells Syndrome
    Arthritis & Rheumatism, 2013
    Co-Authors: Assen Koitschev, Stefan K. Plontke, Sandra Hansmann, Katharina Ummenhofer, Christiane Koitschev, Ina Koetter, Eva Angermair, Susanne M. Benseler
    Abstract:

    Objective Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin-1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes. Methods A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype-specific risk of progression of hearing loss was determined. Results A total of 33 patients ages 3–75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss. Conclusion Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions.

  • Progressive familial hearing loss in Muckle-Wells Syndrome
    Acta oto-laryngologica, 2012
    Co-Authors: Assen Koitschev, Stefan K. Plontke, Sandra Hansmann, Christiane Koitschev, Susanne M. Benseler, Katharina Gramlich, Ina Koetter, Jasmin B. Kuemmerle-deschner
    Abstract:

    Abstract Conclusion: The age-dependent disease progression requires accelerating diagnosis of Muckle-Wells Syndrome (MWS) in order to start treatment as early as possible. The most frequent, but not obligate symptoms are familial fatigue, hearing loss, and arthralgia. The design of further clinical trials should focus on hearing in order to document the long-term effect of anti-interleukin (IL)-1 drugs on hearing preservation. Objectives: This paper describes the otologic features of a genetically defined Syndrome causing progressive hearing loss by cochlear degeneration. This is the first study reporting the pretreatment otologic presentation of a selected population with familial MWS. Methods: A single-center cohort was examined by audiologic and neurotologic methods including pure tone audiograms, vestibular testing, and tinnitus questionnaire. The audiograms of members of the same family were compared to describe the family-specific risk of hearing loss progression. Results: Nineteen patients (aged 3–...

  • nlrp3 e311k mutation in a large family with Muckle Wells Syndrome description of a heterogeneous phenotype and response to treatment
    Arthritis Research & Therapy, 2011
    Co-Authors: Peter Lohse, Katharina Ummenhofer, Ina Koetter, Fabian Reess, Anja Bialkowski, Nicolai Tzaribachev, Guenther E Dannecker, Silvia Koch, Susanne M. Benseler
    Abstract:

    Introduction: Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. Methods: A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. Results: All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/ E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-a, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. Conclusions: The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

  • nlrp3 e311k mutation in a large family with Muckle Wells Syndrome description of a heterogeneous phenotype and response to treatment
    Arthritis Research & Therapy, 2011
    Co-Authors: Jasmin B Kuemmerledeschner, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Anja Bialkowski, Nicolai Tzaribachev, Guenther E Dannecker, Silvia Koch, Susanne M. Benseler
    Abstract:

    Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

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  • early detection of sensorineural hearing loss in Muckle Wells Syndrome
    Pediatric Rheumatology, 2015
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Stefan K. Plontke, Norbert Deschner, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Christiane Koitschev, Susanne M. Benseler
    Abstract:

    Muckle-Wells-Syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5–4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response.

  • challenges in diagnosing Muckle Wells Syndrome identifying two distinct phenotypes
    Arthritis Care and Research, 2014
    Co-Authors: Samuel Dembi Samba, Pascal N. Tyrrell, Norbert Deschner, Isabelle Marie, Isabelle Konepaut, Susanne M. Benseler
    Abstract:

    Objective The diagnosis of Muckle-Wells Syndrome (MWS) remains challenging due to the clinical heterogeneity and lack of diagnostic criteria. The aims of this study were to describe key elements of the diagnostic evaluation process in MWS and compare identified variables between patients diagnosed in childhood and adulthood. Methods A cohort study of consecutive patients with a clinical and genetic diagnosis of MWS was conducted at 2 reference centers for autoinflammatory diseases. Demographic information, clinical presentation, access to care, and preclinical evaluation variables were captured. Presenting symptoms were compared between groups of patients diagnosed in childhood and adulthood. Prediction analysis explored variables associated with late diagnosis. Correspondence analysis identified clinical phenotypes. Results A total of 34 MWS patients were included (16 males, 18 females) and median age at diagnosis was 31.5 years (range 0.5–75 years). Patients diagnosed during childhood reported musculoskeletal symptoms (62%), rash (62%), fever (54%), and abdominal pain (31%). Those diagnosed as adults described musculoskeletal symptoms (86%), rash (67%), hearing loss (52%), and fatigue (29%). Hearing loss was associated with late diagnosis, while access-to-care variables were not predictive. Correspondence analysis identified distinct clinical phenotypes as follows: an “inflammatory phenotype” (most commonly seen in patients diagnosed in childhood and characterized by relapsing fever and abdominal pain), an intermediate phenotype, and an “organ-disease” phenotype in patients diagnosed during adulthood and characterized by fatigue and hearing loss. Conclusion Distinct clinical phenotypes were identified in patients with MWS. These are closely related to age at diagnosis. The presence of these phenotypes has to be considered when developing diagnostic criteria for MWS.

  • treatment of Muckle Wells Syndrome analysis of two il 1 blocking regimens
    Arthritis Research & Therapy, 2013
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Helmut Wittkowski, Christoph Deuter
    Abstract:

    Objectives: Muckle-Wells Syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1b monoclonal antibody, can abolish excess IL-1b. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results: The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumabtreated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

  • efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle Wells Syndrome
    Arthritis & Rheumatism, 2011
    Co-Authors: Pascal N. Tyrrell, Peter Lohse, Ina Koetter, Helmut Wittkowski, Anja Bialkowski, Nicolai Tzaribachev, Assen Koitchev, Christoph Deuter, Dirk Foell
    Abstract:

    Objective Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. Methods A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. Results A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5–14 months). The median followup was 11 months (range 5–14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. Conclusion Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

  • risk factors for severe Muckle Wells Syndrome
    Arthritis & Rheumatism, 2010
    Co-Authors: Jasmin Kummerledeschner, Pascal N. Tyrrell, Peter Lohse, Fabian Reess, I Kotter, H J Girschick, Christian Huemer, Gerd Horneff, Johannespeter Haas, Assen Koitschev
    Abstract:

    Objective Muckle-Wells Syndrome (MWS) is an inherited autoinflammatory disease resulting in excessive interleukin-1 release. It is unknown whether demographic, clinical, or laboratory characteristics at the time of diagnosis may identify patients who are at high risk for severe disease activity. This study was undertaken to analyze clinical and laboratory features of MWS, compare genetically defined subcohorts, and identify risk factors for severe MWS. Methods A multicenter cohort study of consecutive MWS patients was performed. Parameters assessed included clinical features, MWS Disease Activity Score (MWS-DAS), inflammation markers, and cytokine levels. E311K mutation–positive patients were compared with E311K mutation–negative patients. Putative risk factors for severe MWS (defined as an MWS-DAS score of ≥10) were assessed in univariate analyses, and significant predictors were entered into a multivariate model. Results Thirty-two patients (15 male and 17 female) were studied. The most frequent organ manifestations were musculoskeletal symptoms and eye and skin disorders. Renal disease and hearing loss were seen in >50% of the patients. Genetically defined subcohorts had distinct phenotypes. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis were female sex, hearing loss, musculoskeletal disease, increased erythrocyte sedimentation rate, and low hemoglobin level. Female sex and hearing loss remained significant after adjustment for age in a multivariate model (relative risk 1.8 and 2.6, respectively). Conclusion MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high-risk group.