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Papers by Harald Burkhardt

Research paper thumbnail of Prospektive multizentrische Studie bei Patienten mit früher rheumatoider Arthritis - Prognosefaktoren und Verlaufsparameter : Abschlußbericht 2008

Research paper thumbnail of Innovative Imaging Technique for Visualization of Vascularization and Established Methods for Detection of Musculoskeletal Inflammation in Psoriasis Patients

Frontiers in Medicine, 2020

Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the ... more Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations (e.g., oligo-or polyarthritis, enthesitis, dactylitis, and axial inflammation), early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors (e.g., genetic, environmental) on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase (soluble and imaging biomarkers detectable, no clinical symptoms) and the prodromal phase (imaging biomarkers detectable, unspecific musculoskeletal symptoms such as arthralgia and fatigue). To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be Köhm et al. Imaging for Musculoskeletal-Inflammation in PsO identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease.

Research paper thumbnail of IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells

Cell Reports, 2019

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. Howe... more Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or gd T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon gd T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress gd T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by gd T cells. Our findings indicate a role for IL-38 in the regulation of gd T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.

Research paper thumbnail of Hautmalignome und immunmodulierende Antirheumatikatherapie

Zeitschrift für Rheumatologie, 2016

Research paper thumbnail of O53. PTPN22 is Associated with Susceptibility to Psoriatic Arthritis but not Psoriasis: Evidence for a Further PSA-Specific Risk Locus

Rheumatology, 2015

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psorias... more Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis with the prevalence rate of PsA in psoriasis i48 Thursday

Research paper thumbnail of Triple polypeptide complexes

Research paper thumbnail of Does Concomitant Methotrexate with Adalimumab Influence Treatment Outcomes in Patients with Psoriatic Arthritis? Data from a Large Observational Study

The Journal of rheumatology, Jan 15, 2015

To examine the influence of concomitant methotrexate (MTX) with adalimumab (ADA) on outcomes in p... more To examine the influence of concomitant methotrexate (MTX) with adalimumab (ADA) on outcomes in patients with psoriatic arthritis (PsA) using data from an observational study of ADA. Data from a German noninterventional study of patients with PsA starting treatment with ADA were analyzed retrospectively for effects of concomitant MTX on key outcomes, including Disease Activity Score-28 joints, tender and swollen joint counts, skin assessments, and safety. Patients were categorized into those with symptoms of axial involvement and those with no symptoms of axial involvement as judged by the examining clinician. A total of 1455 patients met the study criteria, 296 with axial involvement (ADA monotherapy = 165; plus MTX = 131) and 1159 with no axial involvement (ADA monotherapy = 658; plus MTX = 501). ADA, alone or combined with MTX, resulted in strong and comparable reductions in disease activity measures in patients with and those without axial disease over 24 months of therapy. In m...

Research paper thumbnail of Aktualisiertes Therapieschema der Rheumatoiden Arthritis. Ergebnisse eines Konsensusprozesses deutscher Rheumatologen 2009

Aktuelle Rheumatologie, 2009

• ▶ rheumatoid arthritis • ▶ therapy • ▶ biologicals • ▶ recommendations • ▶ consensus Aktualisie... more • ▶ rheumatoid arthritis • ▶ therapy • ▶ biologicals • ▶ recommendations • ▶ consensus Aktualisiertes Therapieschema der Rheumatoiden Arthritis. Ergebnisse eines Konsensusprozesses deutscher Rheumatologen 2009 Recommendations for the Treatment of Rheumatoid Arthritis. Results from a German Consensus Conferenence: Update 2009 einem Wandel. Verschiedene Aspekte tragen zu dieser Dynamik bei: Die Erkennung von Verdachtsf ä llen durch Haus ä rzte und Orthop ä den hat sich in den vergangenen Jahren verbessert und die Einrichtung von Rheuma-Fr ü herken-Einleitung &

Research paper thumbnail of Anti-citrullinated protein antibodies are linked to erosive disease in an observational study of patients with psoriatic arthritis

Rheumatology (Oxford, England), Jan 21, 2016

ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the assoc... more ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and si...

Research paper thumbnail of Zytopenien

Zeitschrift für Rheumatologie, 2017

Die Anämie ist eine typische Komorbidität entzündlich rheumatischer Erkrankungen wie der rheumato... more Die Anämie ist eine typische Komorbidität entzündlich rheumatischer Erkrankungen wie der rheumatoiden Arthritis mit schweregradabhängig negativen Auswirkungen auf die körperliche Leistungsfähigkeit, das Allgemeinbefinden und die Lebensqualität. Die Anämie ist dabei häufig Ausdruck der Aktivität und Schwere der zugrunde liegenden rheumatischen Inflammationserkrankung und reflektiert die Wirkungen proinflammatorischer Zytokine auf den Eisenstoffwechsel und die Erythropoese. In der klinischen Praxis gilt es jedoch zu beachten, dass multiple weitere Faktoren zur Entwicklung einer Anämie beitragen können, wie u. a. Vitaminmangelzustände, Blutverluste, Hämolyse oder unerwünschte Medikamentenwirkungen. Somit ist es wichtig, die multifaktorielle Pathogenese der Anämie als komplexes medizinisches Problem für die Beurteilung und therapeutische Entscheidungsfindung im Einzelfall zu berücksichtigen.

Research paper thumbnail of Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes

Science Advances, 2018

Inducible nitric oxide from skin macrophages promotes IL-17 release and psoriatic arthritis by in... more Inducible nitric oxide from skin macrophages promotes IL-17 release and psoriatic arthritis by innate lymphoid cells.

Research paper thumbnail of Modulation of granulocyte-endothelium interactions by antileukoproteinase: inhibition of anti-type II collagen antibody-induced leukocyte attachment to the synovial endothelium

Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has ... more Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has been shown to have antiinflammatory properties in addition to its antiproteolytic activity. On the basis of its potential to block anti-collagen type II (CII) antibody-induced arthritis (CAIA) and to suppress the conformational activation of β 2-integrins in leukocytes, the present study was undertaken to investigate its interference with leukocyte adherence to cytokine-activated endothelium. The potential of recombinant ALP to block the interactions of leukocytes with the endothelial lining was concomitantly investigated in vitro and in vivo. Thus, intravital fluorescence microscopic imaging of leukocyte rolling and firm adhesion to postcapillary venules were performed in the knee joints of DBA1/J mice after intravenous injection of anti-CII mAbs. An IL-1β-activated endothelial layer formed by a murine glomerular cell line (glEND.2) was used to assay the interaction with human leukocytes in vitro. Electromobility shift and luciferase reporter gene assays permitted the analysis of cytokine-induced activation of the NF-κB pathway. Fluorescence-activated cell sorting was applied to determine endothelial E-selectin expression. Leukocyte rolling and firm adhesion to the synovial endothelium in an early response to the anti-CII antibody transfer were significantly decreased in ALP-pretreated mice. Concomitantly, ALP suppressed the IL-1β-induced NF-κB activation and the upregulation of E-selectin expression in glEND.2 cells in vitro. These findings support the notion that the newly uncovered properties of ALP to interfere with cytokine signalling and upregulation of adhesion molecules in endothelial cells are likely to contribute to the therapeutic potential of ALP in immune-complex-induced tissue injury.

Research paper thumbnail of A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts

Cells

Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via t... more Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the con...

Research paper thumbnail of NF- B inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF- B in immune-mediated diseases

Proceedings of the National Academy of Sciences, 2013

Research paper thumbnail of Cell-Type Targeted NF-kappaB Inhibition for the Treatment of Inflammatory Diseases

Cells

Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenes... more Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the “sneaking ligand” approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The protot...

Research paper thumbnail of Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups

Research paper thumbnail of Cell adhesion-induced transient interaction of ADAM15 with poly(A) binding protein at the cell membrane colocalizes with mRNA translation

Research paper thumbnail of Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis

Journal of Investigative Dermatology

Research paper thumbnail of Use of a “critical difference” statistical criterion improves the predictive utility of the Health Assessment Questionnaire-Disability Index score in patients with rheumatoid arthritis

BMC Rheumatology

Background The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functi... more Background The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functional status in rheumatoid arthritis (RA), but the change required for meaningful improvements remains unclear. A minimum clinically important difference (MCID) of 0.22 is frequently used in RA trials. The aim of this study was to determine a statistically defined critical difference for HAQ-DI (HAQ-DI-dcrit) and evaluate its association with therapeutic outcomes. Methods We retrospectively analyzed data from adult German patients with RA enrolled in a multicenter observational trial in which they received adalimumab therapy at the decision of the treating clinician during routine clinical care. The HAQ-DI-dcrit, defined as the minimum change that can be reliably discriminated from random long-term variations in patients on stable therapy, was determined by evaluating intra-individual variation in patient scores. Other outcomes of interest included Disease Activity Score-28 joints and pat...

Research paper thumbnail of Addition or removal of concomitant methotrexate alters adalimumab effectiveness in rheumatoid arthritis but not psoriatic arthritis

Scandinavian Journal of Rheumatology

Research paper thumbnail of Prospektive multizentrische Studie bei Patienten mit früher rheumatoider Arthritis - Prognosefaktoren und Verlaufsparameter : Abschlußbericht 2008

Research paper thumbnail of Innovative Imaging Technique for Visualization of Vascularization and Established Methods for Detection of Musculoskeletal Inflammation in Psoriasis Patients

Frontiers in Medicine, 2020

Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the ... more Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations (e.g., oligo-or polyarthritis, enthesitis, dactylitis, and axial inflammation), early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors (e.g., genetic, environmental) on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase (soluble and imaging biomarkers detectable, no clinical symptoms) and the prodromal phase (imaging biomarkers detectable, unspecific musculoskeletal symptoms such as arthralgia and fatigue). To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be Köhm et al. Imaging for Musculoskeletal-Inflammation in PsO identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease.

Research paper thumbnail of IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells

Cell Reports, 2019

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. Howe... more Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or gd T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon gd T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress gd T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by gd T cells. Our findings indicate a role for IL-38 in the regulation of gd T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.

Research paper thumbnail of Hautmalignome und immunmodulierende Antirheumatikatherapie

Zeitschrift für Rheumatologie, 2016

Research paper thumbnail of O53. PTPN22 is Associated with Susceptibility to Psoriatic Arthritis but not Psoriasis: Evidence for a Further PSA-Specific Risk Locus

Rheumatology, 2015

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psorias... more Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis with the prevalence rate of PsA in psoriasis i48 Thursday

Research paper thumbnail of Triple polypeptide complexes

Research paper thumbnail of Does Concomitant Methotrexate with Adalimumab Influence Treatment Outcomes in Patients with Psoriatic Arthritis? Data from a Large Observational Study

The Journal of rheumatology, Jan 15, 2015

To examine the influence of concomitant methotrexate (MTX) with adalimumab (ADA) on outcomes in p... more To examine the influence of concomitant methotrexate (MTX) with adalimumab (ADA) on outcomes in patients with psoriatic arthritis (PsA) using data from an observational study of ADA. Data from a German noninterventional study of patients with PsA starting treatment with ADA were analyzed retrospectively for effects of concomitant MTX on key outcomes, including Disease Activity Score-28 joints, tender and swollen joint counts, skin assessments, and safety. Patients were categorized into those with symptoms of axial involvement and those with no symptoms of axial involvement as judged by the examining clinician. A total of 1455 patients met the study criteria, 296 with axial involvement (ADA monotherapy = 165; plus MTX = 131) and 1159 with no axial involvement (ADA monotherapy = 658; plus MTX = 501). ADA, alone or combined with MTX, resulted in strong and comparable reductions in disease activity measures in patients with and those without axial disease over 24 months of therapy. In m...

Research paper thumbnail of Aktualisiertes Therapieschema der Rheumatoiden Arthritis. Ergebnisse eines Konsensusprozesses deutscher Rheumatologen 2009

Aktuelle Rheumatologie, 2009

• ▶ rheumatoid arthritis • ▶ therapy • ▶ biologicals • ▶ recommendations • ▶ consensus Aktualisie... more • ▶ rheumatoid arthritis • ▶ therapy • ▶ biologicals • ▶ recommendations • ▶ consensus Aktualisiertes Therapieschema der Rheumatoiden Arthritis. Ergebnisse eines Konsensusprozesses deutscher Rheumatologen 2009 Recommendations for the Treatment of Rheumatoid Arthritis. Results from a German Consensus Conferenence: Update 2009 einem Wandel. Verschiedene Aspekte tragen zu dieser Dynamik bei: Die Erkennung von Verdachtsf ä llen durch Haus ä rzte und Orthop ä den hat sich in den vergangenen Jahren verbessert und die Einrichtung von Rheuma-Fr ü herken-Einleitung &

Research paper thumbnail of Anti-citrullinated protein antibodies are linked to erosive disease in an observational study of patients with psoriatic arthritis

Rheumatology (Oxford, England), Jan 21, 2016

ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the assoc... more ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and si...

Research paper thumbnail of Zytopenien

Zeitschrift für Rheumatologie, 2017

Die Anämie ist eine typische Komorbidität entzündlich rheumatischer Erkrankungen wie der rheumato... more Die Anämie ist eine typische Komorbidität entzündlich rheumatischer Erkrankungen wie der rheumatoiden Arthritis mit schweregradabhängig negativen Auswirkungen auf die körperliche Leistungsfähigkeit, das Allgemeinbefinden und die Lebensqualität. Die Anämie ist dabei häufig Ausdruck der Aktivität und Schwere der zugrunde liegenden rheumatischen Inflammationserkrankung und reflektiert die Wirkungen proinflammatorischer Zytokine auf den Eisenstoffwechsel und die Erythropoese. In der klinischen Praxis gilt es jedoch zu beachten, dass multiple weitere Faktoren zur Entwicklung einer Anämie beitragen können, wie u. a. Vitaminmangelzustände, Blutverluste, Hämolyse oder unerwünschte Medikamentenwirkungen. Somit ist es wichtig, die multifaktorielle Pathogenese der Anämie als komplexes medizinisches Problem für die Beurteilung und therapeutische Entscheidungsfindung im Einzelfall zu berücksichtigen.

Research paper thumbnail of Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes

Science Advances, 2018

Inducible nitric oxide from skin macrophages promotes IL-17 release and psoriatic arthritis by in... more Inducible nitric oxide from skin macrophages promotes IL-17 release and psoriatic arthritis by innate lymphoid cells.

Research paper thumbnail of Modulation of granulocyte-endothelium interactions by antileukoproteinase: inhibition of anti-type II collagen antibody-induced leukocyte attachment to the synovial endothelium

Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has ... more Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has been shown to have antiinflammatory properties in addition to its antiproteolytic activity. On the basis of its potential to block anti-collagen type II (CII) antibody-induced arthritis (CAIA) and to suppress the conformational activation of β 2-integrins in leukocytes, the present study was undertaken to investigate its interference with leukocyte adherence to cytokine-activated endothelium. The potential of recombinant ALP to block the interactions of leukocytes with the endothelial lining was concomitantly investigated in vitro and in vivo. Thus, intravital fluorescence microscopic imaging of leukocyte rolling and firm adhesion to postcapillary venules were performed in the knee joints of DBA1/J mice after intravenous injection of anti-CII mAbs. An IL-1β-activated endothelial layer formed by a murine glomerular cell line (glEND.2) was used to assay the interaction with human leukocytes in vitro. Electromobility shift and luciferase reporter gene assays permitted the analysis of cytokine-induced activation of the NF-κB pathway. Fluorescence-activated cell sorting was applied to determine endothelial E-selectin expression. Leukocyte rolling and firm adhesion to the synovial endothelium in an early response to the anti-CII antibody transfer were significantly decreased in ALP-pretreated mice. Concomitantly, ALP suppressed the IL-1β-induced NF-κB activation and the upregulation of E-selectin expression in glEND.2 cells in vitro. These findings support the notion that the newly uncovered properties of ALP to interfere with cytokine signalling and upregulation of adhesion molecules in endothelial cells are likely to contribute to the therapeutic potential of ALP in immune-complex-induced tissue injury.

Research paper thumbnail of A Novel Pro-Inflammatory Mechanosensing Pathway Orchestrated by the Disintegrin Metalloproteinase ADAM15 in Synovial Fibroblasts

Cells

Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via t... more Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the con...

Research paper thumbnail of NF- B inhibitor targeted to activated endothelium demonstrates a critical role of endothelial NF- B in immune-mediated diseases

Proceedings of the National Academy of Sciences, 2013

Research paper thumbnail of Cell-Type Targeted NF-kappaB Inhibition for the Treatment of Inflammatory Diseases

Cells

Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenes... more Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the “sneaking ligand” approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The protot...

Research paper thumbnail of Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups

Research paper thumbnail of Cell adhesion-induced transient interaction of ADAM15 with poly(A) binding protein at the cell membrane colocalizes with mRNA translation

Research paper thumbnail of Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis

Journal of Investigative Dermatology

Research paper thumbnail of Use of a “critical difference” statistical criterion improves the predictive utility of the Health Assessment Questionnaire-Disability Index score in patients with rheumatoid arthritis

BMC Rheumatology

Background The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functi... more Background The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functional status in rheumatoid arthritis (RA), but the change required for meaningful improvements remains unclear. A minimum clinically important difference (MCID) of 0.22 is frequently used in RA trials. The aim of this study was to determine a statistically defined critical difference for HAQ-DI (HAQ-DI-dcrit) and evaluate its association with therapeutic outcomes. Methods We retrospectively analyzed data from adult German patients with RA enrolled in a multicenter observational trial in which they received adalimumab therapy at the decision of the treating clinician during routine clinical care. The HAQ-DI-dcrit, defined as the minimum change that can be reliably discriminated from random long-term variations in patients on stable therapy, was determined by evaluating intra-individual variation in patient scores. Other outcomes of interest included Disease Activity Score-28 joints and pat...

Research paper thumbnail of Addition or removal of concomitant methotrexate alters adalimumab effectiveness in rheumatoid arthritis but not psoriatic arthritis

Scandinavian Journal of Rheumatology