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Holzinger, dirk

Elena Belelli, Chiara Passarelli, Manuela Pardeo, Dirk Holzinger, Fabrizio De Benedetti, Antonella Insalaco
OBJECTIVES: Hyperzincaemia/hypercalprotectinemia (Hz/Hc) syndrome is a recently described condition caused by a specific de novo mutation (E250K) affecting PSTPIP1 gene. It has a phenotype distinct from classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome that includes severe systemic and cutaneous inflammation, hepatosplenomegaly, arthritis without sequelae, pancytopenia and failure to thrive. METHODS: We describe an 8-year-old boy who presented recurrent right knee swelling mimicking septic arthritis and persistent bone marrow involvement, without cutaneous involvement...
June 19, 2017: Clinical and Experimental Rheumatology
Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Ndate Fall, Alexei A Grom, Niklas Gruen, Dirk Foell
OBJECTIVE: Systemic-onset juvenile idiopathic arthritis (JIA) is speculated to follow a biphasic course, with an initial systemic disease phase driven by innate immune mechanisms and interleukin-1β (IL-1β) as a key cytokine and a second chronic arthritic phase that may be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mouse model points to a critical role of IL-17-expressing γ/δ T cells in disease pathology, in humans, both the prevalence of IL-17 and the role of IL-17-producing cells are still unclear...
March 15, 2017: Arthritis & Rheumatology
Meriam Nefla, Dirk Holzinger, Francis Berenbaum, Claire Jacques
Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy)...
November 2016: Nature Reviews. Rheumatology
Miha Lavric, María Auxiliadora Miranda-García, Dirk Holzinger, Dirk Foell, Helmut Wittkowski
Alarmins are endogenous molecules with homeostatic roles that have reached the focus of research in inflammatory arthritis in the last two decades, mostly due to their ability to indicate tissue related damage after active or passive release from injured cells. From HMGB1, S100A8/A9 and S100A12 proteins, over heat-shock proteins (HSPs) and purine metabolites (e.g. uric acid, ATP) to altered matrix proteins and interleukin-33 (IL-33), a number of alarmins have been determined until now as having a role in rheumatoid arthritis, psoriatic and juvenile idiopathic arthritis, as well as spondyloarthritis and gout...
July 2017: Joint, Bone, Spine: Revue du Rhumatisme
Dirk Holzinger, Johannes Roth
PURPOSE OF REVIEW: To give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) and new insights into their pathogenesis. RECENT FINDINGS: In addition to classical pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has been described as a distinct clinical phenotype of PSTPIP1-associated inflammatory diseases (PAID) and other entities are emerging...
September 2016: Current Opinion in Rheumatology
Faekah Gohar, Christoph Kessel, Miha Lavric, Dirk Holzinger, Dirk Foell
BACKGROUND: Diagnosing systemic juvenile idiopathic arthritis (SJIA) can be extremely challenging if typical arthritis is lacking. A variety of biomarkers have been described for the diagnosis and management of SJIA. However, very few markers have been well-validated. In addition, increasing numbers of biomarkers are identified by high throughput or multi-marker panels. METHOD: We identified diagnostic or prognostic biomarkers by systematic literature review, evaluating each according to a predefined level of verification, validation or clinical utility...
2016: Arthritis Research & Therapy
Faekah Gohar, Banu Orak, Tilmann Kallinich, Marion Jeske, Mareike Lieber, Horst von Bernuth, Arnd Giese, Elisabeth Weissbarth-Riedel, Johannes-Peter Haas, Frank Dressler, Dirk Holzinger, Peter Lohse, Ulrich Neudorf, Elke Lainka, Claas Hinze, Katja Masjosthusmann, Christoph Kessel, Toni Weinhage, Dirk Foell, Helmut Wittkowski
OBJECTIVE: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF...
December 2016: Arthritis & Rheumatology
E H Pieter van Dijkhuizen, Juliëtte N Pouw, Andrea Scheuern, Boris Hügle, Sven Hardt, Gerd Ganser, Jasmin Beate Kümmerle-Deschner, Gerd Horneff, Dirk Holzinger, Maja Bulatović Ćalasan, Nico M Wulffraat
OBJECTIVES: Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug (DMARD) in juvenile idiopathic arthritis (JIA). In Dutch patients, MTX intolerance occurred frequently and was associated with subcutaneous (SC) administration. The aim of this study was to assess the prevalence of MTX intolerance and its association with the route of administration in a German cohort of JIA patients. METHODS: A cross-sectional study of JIA patients on MTX was performed...
January 2016: Clinical and Experimental Rheumatology
Karoline Walscheid, Arnd Heiligenhaus, Dirk Holzinger, Johannes Roth, Carsten Heinz, Christoph Tappeiner, Maren Kasper, Dirk Foell
PURPOSE: Juvenile idiopathic arthritis-associated uveitis (JIAU) is the most common uveitis entity in childhood. As S100A8/A9 and S100A12 proteins are valuable biomarkers in childhood arthritis, we investigated the occurrence of these proteins in childhood uveitis. METHODS: Serum samples from patients with JIAU (n = 79) or idiopathic anterior uveitis (IAU, n = 24), as well as from nonuveitic controls (n = 24), were collected. Furthermore, aqueous humor samples (JIAU n = 17, nonuveitic controls n = 16, IAU n = 12) were obtained...
December 2015: Investigative Ophthalmology & Visual Science
Mareike Lieber, Tilmann Kallinich, Peter Lohse, Jens Klotsche, Dirk Holzinger, Dirk Foell, Helmut Wittkowski
OBJECTIVES: To assess subclinical inflammation in heterozygous carriers of Mediterranean fever (MEFV) gene mutations, analysis of classical inflammation markers and S100A12 was performed. METHODS: Exons 2, 3, and 10 of the MEFV gene, C-reactive protein (CRP), serum amyloid A protein (SAA), procalcitonin (PCT), and S100A12 concentrations, erythrocyte sedimentation rate (ESR), and differential blood count were analysed in apparently healthy parents (n=26) of homozygous children with familial Mediterranean fever (FMF)...
November 2015: Clinical and Experimental Rheumatology
Janneke Anink, Lisette W A Van Suijlekom-Smit, Marieke H Otten, Femke H M Prince, Marion A J van Rossum, Koert M Dolman, Esther P A H Hoppenreijs, Rebecca ten Cate, Simona Ursu, Lucy R Wedderburn, Gerd Horneff, Michael Frosch, Thomas Vogl, Faekah Gohar, Dirk Foell, Johannes Roth, Dirk Holzinger
INTRODUCTION: Approximately 30% of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped. We tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy. METHODS: Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed...
2015: Arthritis Research & Therapy
Laura B E Kienhorst, Ellen van Lochem, Wietske Kievit, Nicola Dalbeth, Marilyn E Merriman, Amanda Phipps-Green, Arnoud Loof, Waander van Heerde, Sita Vermeulen, Lisa K Stamp, Elly van Koolwijk, Jacqueline de Graaf, Dirk Holzinger, Johannes Roth, Hein J E M Janssens, Tony R Merriman, Jasper C A Broen, Matthijs Janssen, Timothy R D J Radstake
OBJECTIVE: The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients. METHODS: We studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls. We measured circulating levels of interleukin-8 (IL-8)/CXCL8, IL-1β, IL-6, IL-10, IL-12, and tumor necrosis factor, after which we performed proteome-wide analysis in a selection of samples to identify proteins that were possibly prognostic for the development of comorbidities...
December 2015: Arthritis & Rheumatology
Heleen D de Koning, Joost Schalkwijk, Monique Stoffels, Johanna Jongekrijg, Joannes F M Jacobs, Eugène Verwiel, Hans J P M Koenen, Frank Preijers, Dirk Holzinger, Irma Joosten, Jos W M van der Meer, Anna Simon
INTRODUCTION: Schnitzler's syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largely unknown. Here we studied the effect of in-vivo IL-1 inhibition on serum markers of inflammation and cellular immune responses. METHODS: Eight patients with SchS received monthly subcutaneous (s...
July 22, 2015: Arthritis Research & Therapy
Gunnar Wichmann, Maciej Rosolowski, Knut Krohn, Markus Kreuz, Andreas Boehm, Anett Reiche, Ulrike Scharrer, Dirk Halama, Julia Bertolini, Ulrike Bauer, Dana Holzinger, Michael Pawlita, Jochen Hess, Christoph Engel, Dirk Hasenclever, Markus Scholz, Peter Ahnert, Holger Kirsten, Alexander Hemprich, Christian Wittekind, Olf Herbarth, Friedemann Horn, Andreas Dietz, Markus Loeffler
Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively)...
December 15, 2015: International Journal of Cancer. Journal International du Cancer
Dirk Holzinger, Christoph Kessel, Alessia Omenetti, Marco Gattorno
Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies...
October 2015: Nature Reviews. Rheumatology
Dirk Holzinger, Selina Kathleen Fassl, Wilco de Jager, Peter Lohse, Ute F Röhrig, Marco Gattorno, Alessia Omenetti, Sabrina Chiesa, Francesca Schena, Judith Austermann, Thomas Vogl, Douglas B Kuhns, Steven M Holland, Carlos Rodríguez-Gallego, Ricardo López-Almaraz, Juan I Arostegui, Elena Colino, Rosa Roldan, Smaragdi Fessatou, Bertrand Isidor, Sylvaine Poignant, Koichi Ito, Hans-Joerg Epple, Jonathan A Bernstein, Michael Jeng, Jennifer Frankovich, Geraldina Lionetti, Joseph A Church, Peck Y Ong, Mona LaPlant, Mario Abinun, Rod Skinner, Venetia Bigley, Ulrich J Sachs, Claas Hinze, Esther Hoppenreijs, Jan Ehrchen, Dirk Foell, Jae Jin Chae, Amanda Ombrello, Ivona Aksentijevich, Cord Sunderkoetter, Johannes Roth
BACKGROUND: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome...
November 2015: Journal of Allergy and Clinical Immunology
Ivan Caiello, Gaetana Minnone, Dirk Holzinger, Thomas Vogl, Giusi Prencipe, Antonio Manzo, Fabrizio De Benedetti, Raffaele Strippoli
The role of Interleukin(IL)-6 in the pathogenesis of joint and systemic inflammation in rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (s-JIA) has been clearly demonstrated. However, the mechanisms by which IL-6 contributes to the pathogenesis are not completely understood. This study investigates whether IL-6 affects, alone or upon toll like receptor (TLR) ligand stimulation, the production of inflammatory cytokines and chemokines in human peripheral blood mononuclear cells (PBMCs), synovial fluid mononuclear cells from JIA patients (SFMCs) and fibroblast-like synoviocytes from rheumatoid arthritis patients (RA synoviocytes) and signalling pathways involved...
2014: PloS One
Ivy Y Choi, Danielle M Gerlag, Dirk Holzinger, Johannes Roth, Paul P Tak
OBJECTIVE: The change in number of CD68-positive sublining macrophages in serial synovial biopsies has been successfully used to discriminate on the group level between effective and ineffective treatment during early drug development in rheumatoid arthritis (RA) patients. Measurement of a soluble biomarker would clearly have practical advantages. Therefore, we investigated the sensitivity to change of myeloid related protein (MRP)8/14 in serum. METHODS: 139 RA patients who received known effective biologics (infliximab, adalimumab and rituximab) and 28 RA patients who received placebo/ineffective therapies were included...
2014: PloS One
Sebastiaan J Vastert, Wilco de Jager, Bo Jan Noordman, Dirk Holzinger, Wietse Kuis, Berent J Prakken, Nico M Wulffraat
OBJECTIVE: To conduct a prospective cohort study using anakinra, a recombinant IL-1 receptor antagonist (IL-1Ra), as first-line therapy in patients with new-onset systemic juvenile idiopathic arthritis (JIA). METHODS: Therapy with recombinant IL-1Ra (2 mg/kg) was initiated in 20 patients who fulfilled the International League of Associations for Rheumatology criteria for systemic JIA, before systemic steroid treatment was administered. Patients were monitored clinically and immunologically...
April 2014: Arthritis & Rheumatology
Dirk Holzinger, Nadine Nippe, Thomas Vogl, Kristina Marketon, Vijayashree Mysore, Toni Weinhage, Nicola Dalbeth, Bregina Pool, Tony Merriman, Dominique Baeten, Annette Ives, Nathalie Busso, Dirk Foell, Sylvette Bas, Cem Gabay, Johannes Roth
OBJECTIVE: Monosodium urate monohydrate (MSU) crystal-induced interleukin-1β (IL-1β) secretion is a critical factor in the pathogenesis of gout. However, without costimulation by a proIL-1β-inducing factor, MSU crystals alone are insufficient to induce IL-1β secretion. The responsible costimulatory factors that act as a priming endogenous signal in vivo are not yet known. We undertook this study to analyze the costimulatory properties of myeloid-related protein 8 (MRP-8) and MRP-14 (endogenous Toll-like receptor 4 [TLR-4] agonists) in MSU crystal-induced IL-1β secretion and their relevance in gout...
May 2014: Arthritis & Rheumatology
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