Dirk Holzinger

University Hospital Essen | UK Essen · Clinic for Pediatrics III

Das Makrophagenaktivierungssyndrom (MAS) ist eine Form der sekundären hämophagozytischen Lymphohistiozytose (HLH) und eine potenziell tödliche Komplikation entzündlicher Erkrankungen bei Kindern. MAS tritt am häufigsten bei der systemischen Juvenilen Idiopathischen Arthritis (sJIA) auf. Ungefähr 10 % der Kinder entwickeln ein fulminantes MAS, 30–40...

Die systemische juvenilen idiopathische Arthritis (sJIA) wird durch eine Arthritis, remittierendes Fieber sowie ein typisches flüchtiges Exanthem (sogenannter Rash) charakterisiert. Die sJIA gehört zu den seltenen Formen der JIA und wird als autoinflammatorische Systemerkrankung verstanden. Die Voraussetzung für eine erfolgreiche Therapie ist eine...

The objective of this study was to determine the effectiveness of MRP8/14 as a predictor of disease flare in patients with juvenile idiopathic arthritis (JIA) following the withdrawal of methotrexate (MTX) in a routine clinical setting. All MRP8/14 tests performed at a single centre in a 27-month period were considered for analysis. Patients were a...

Objectives To investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA). Methods This multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patie...

Objective Systemic juvenile idiopathic arthritis (sJIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. Previous work indicated decreased IFNγ-expression by T helper (Th) cells in sJIA. Here, we hypothesized this to result from aberrant or incomplete Th cell polarization. Methods Cells or sera were...

Background: Rituximab (RTX) is used in cancer therapy as well as in the treatment of autoimmune diseases and alloimmune responses after transplantation. It depletes the disease-causing B cells by binding to the CD (cluster of differentiation) 20 antigen. We evaluate different pediatric treatment protocols (via fixed treatment schedule, B cell- or s...

Objectives Differential diagnosis in children with prolonged fever is challenging. In particular, differentiating systemic-onset juvenile idiopathic arthritis (SJIA) from infectious diseases is difficult. Biomarkers are needed supporting the diagnostic work-up. The aim of this study was to validate the usefulness of MRP8/14 measurements in the diag...

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alte...

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alte...

Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrex...

Background Heterozygous germline mutations in cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently used with variable effectiveness. Bjective T...

Background Rubella virus-induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. Objective To understand the defective effector mechanism allowing r...

Background: Cytokine storm syndromes are life-threatening complications which can occur in children with rheumatic conditions (macrophage activation syndrome, MAS), inherited cytotoxicity defects (primary haemophagocytic lymphohistiocytosis, pHLH) or in course of infection or malignancies (secondary HLH, sHLH). To adequately steer subsequent treatm...

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be de...

ZUSAMMENFASSUNG Die Behandlung der juvenilen idiopathischen Arthritis (JIA) hat sich in den vergangenen 2 Jahrzehnten u. a. durch die Verfügbarkeit neuer Substanzen entscheidend verändert. Trotz vorhandener Zulassungen, die sich teilweise aus der Behandlung der rheumatoiden Arthritis ableiten, sind zur Einordnung der vorhandenen Evidenz Leitlinien...

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural...

Background An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunological phenotypes. Objective We set out to characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods In a world-wide collaborative effort, we evaluated 231 individuals...

Background Scavenger receptor CD163 is exclusively expressed on monocytes/macrophages and is widely used as a marker for alternatively activated macrophages. However, the role of CD163 is not yet clear. Objectives We examined the function of CD163 in steady-state as well as in sterile and infectious inflammation. Methods Expression of CD163 was a...

Background: Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestation...

Rationale: Interleukin (IL) 18 is a member of the IL-1 cytokine family and elevated blood IL-18 concentrations associate with disease activity in Macrophage Activation Syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions. Objective: While recent investigations provide mechanistic evidence for a contribution of I...

Objectives The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of pat...

Objective Systemic juvenile Idiopathic Arthritis (JIA) is a multifactorial autoinflammatory disease with an historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after one year of therapy. Our treat‐to‐target approach, using recombinant interleukin‐1 receptor antagonist (rIL‐1RA...

Autoimmune and auto-inflammatory diseases in children are causing chronic inflammation, organ damage, and pain. Although several options for treatment are nowadays available a significant number of patients does not respond sufficiently to current therapies. In these diseases inflammatory processes are triggered by numerous exogenous and endogenous...

Background: To our knowledge, the characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate, with a cross-sectional study, the prevalence of disease categories, treatment methods, and disease status in patients from across different geographical areas and from countries with diverse wea...

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome was the first described autoinflammatory disease caused by mutations in the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1, also known as CD2BP1) gene. However, in the last years, the spectrum of PSTPIP1-associated inflammatory diseases (PAID) has expanded encom...

Among the putative markers for autoinflammatory diseases, studies on phagocyte-derived S100 proteins (S100A8/A9, S100A12: calgranulins) are the most advanced to date. Translational studies have suggested an important role for these danger-associated molecular pattern (DAMP) molecules as robust inflammation biomarkers.

S100A8/A9 and S100A12 are released from activated monocytes and granulocytes and act as proinflammatory endogenous toll-like receptor (TLR)4-ligands. S100 serum concentrations correlate with disease activity, both during local and systemic inflammatory processes. In some autoinflammatory diseases such as familial Mediterranean fever (FMF) or system...

S100A12 is highly overexpressed in certain autoinflammatory diseases. Here we describe, that upon cellular release Ca2+ and Zn2+ can operate as molecular switch rendering S100A12 into a toll-like receptor 4-ligand to trigger sterile inflammation.

Background Systemic juvenile idiopathic arthritis (SJIA) is a childhood rheumatic auto-inflammatory disorder of largely unknown pathogenesis. The presence of fever, rash and arthritis support a diagnosis of SJIA, though early in disease arthritis may be minimal, complicating the exclusion of alternative diagnoses such as infection. Furthermore, two...

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the...

Globalization and migration promote the spread of Panton-Valentine leukocidin (PVL)-positive Staphylococcus aureus strains. The toxin PVL is linked to the development of thrombosis in association with osteomyelitis. The mechanisms by which PVL drives thrombosis development are however still unknown. We demonstrate that PVL-damaged neutrophils activ...

Background: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmo...

Objective: Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted....

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mec...

Mutations in the PSTPIP1 gene encoding proline-serine-threonine-phosphatase interactive protein 1 were first identified in an autosomal dominant syndrome called PAPA associated with pyogenic sterile arthritis, pyoderma gangrenosum (PG) and cystic acne.(1,2) . We report a patient with an autoinflammatory syndrome called PSTPIP1-associated myeloid-re...

Objective: To characterize peripheral blood monocytes in uveitis associated with juvenile idiopathic arthritis (JIAU). Methods: Peripheral blood monocytes from children with JIA (either with (n=18) or without uveitis (n=11)), idiopathic anterior uveitis (IAU; n=12) and healthy controls (n=11) were analyzed by flow cytometry. Results: Percentag...

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, hepatosplen...

Objective: Systemic-onset juvenile idiopathic arthritis (sJIA) is speculated to follow a biphasic course with an initial systemic disease phase driven by innate immune mechanisms and interleukin (IL)-1β as a key cytokine, while a second chronic arthritic phase may be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mo...

Les alarmines sont des molécules endogènes à rôles homéostatiques étudiées au cours de récents programmes de recherche sur l’arthrite inflammatoire dans les deux dernières décennies. La raison principale de cet intérêt repose sur leur capacité à alerter le système immunitaire après lésions tissulaires et leur libération active ou passive de ces mol...

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 response...

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 m...

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, P...

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...

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...

Objectives: Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. Methods:...

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 uv...

Inflammatory disorders of childhood, such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD) are a challenge for laboratory diagnostics. Firstly, the classical inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) often inadequately reflect disease activity but on the other hand the...

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, erythro...

Psoriasis is a chronic skin disease with deregulation of proteins in the immune system. These proteins include members of the heterogeneous S100 family, which have been discussed as potential biomarkers for disease severity. The aim of this study was to evaluate the impact of S100A7, S100A8, S100A9 and S100A12 as possible markers for disease activi...

Macrophage activation syndrome is a severe complication of autoimmune and autoinflammatory disease. MAS is most strongly associated with systemic juvenile idiopathic arthritis (sJIA) but can also be seen in Kawasaki disease, SLE or IBD. Clinically, MAS is strikingly similar to hemophagocytic lymphohistiocytosis (HLH) and the initial differentiation...

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. Samples from 88...

The frequent association with the metabolic syndrome and cardiovascular disease (CVD) suggest a systemic component in gout. Our objective was to study whether circulating pro-inflammatory cytokines are associated with comorbidities in gout patients. We studied 330 gout patients from three independent cohorts and compared those with 144 healthy indi...

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...

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...

Background Familial Mediterranean fever (FMF) and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome are inherited autoinflammatory diseases. FMF patients have mutations in pyrin, a protein that has been suggested to play a role in the regulation of the inflammasome, PAPA patients have mutations in PSTPIP1, which interacts with pyri...

Background Familial Mediterranean Fever (FMF) is an autoinflammatory disorder associated with MEFV pyrin-encoding gene mutations. S100A12 is a pro-inflammatory “damage associated molecular pattern” molecule and is strongly elevated in active FMF Objectives To investigate the association between genotype and S100A12 secretion in clinically active, i...

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: Proli...

Chronisch-entzündliche Erkrankungen des Kindesalters wie die juvenile idiopathische Arthritis (JIA) oder chronisch-entzündliche Darmerkrankungen (CED) sind eine Herausforderung an die Labordiagnostik. Zum einen messen klassische Entzündungsmarker wie C-reaktives Protein (CRP) und Blutkörperchensenkungsgeschwindigkeit (BSG) die Krankheitsaktivität h...

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 o...