@article{vonKriesWeissFalkenhorstetal.2011, author = {von Kries, R{\"u}diger and Weiss, Susanne and Falkenhorst, Gerhard and Wirth, Stephan and Kaiser, Petra and Huppertz, Hans-Iko and Tenenbaum, Tobias and Schroten, Horst and Streng, Andrea and Liese, Johannes and Shai, Sonu and Niehues, Tim and Girschick, Hermann and Kuscher, Ellen and Sauerbrey, Axel and Peters, Jochen and Wirsing von Koenig, Carl Heinz and R{\"u}ckinger, Simon and Hampl, Walter and Michel, Detlef and Mertens, Thomas}, title = {Post-Pandemic Seroprevalence of Pandemic Influenza A (H1N1) 2009 Infection (Swine Flu) among Children < 18 Years in Germany}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0023955}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141698}, pages = {e23955}, year = {2011}, abstract = {Background: We determined antibodies to the pandemic influenza A (H1N1) 2009 virus in children to assess: the incidence of (H1N1) 2009 infections in the 2009/2010 season in Germany, the proportion of subclinical infections and to compare titers in vaccinated and infected children. Methodology/Principal Findings: Eight pediatric hospitals distributed over Germany prospectively provided sera from in-or outpatients aged 1 to 17 years from April 1(st) to July 31(st) 2010. Vaccination history, recall of infections and sociodemographic factors were ascertained. Antibody titers were measured with a sensitive and specific in-house hemagglutination inhibition test (HIT) and compared to age-matched sera collected during 6 months before the onset of the pandemic in Germany. We analyzed 1420 post-pandemic and 300 pre-pandemic sera. Among unvaccinated children aged 1-4 and 5-17 years the prevalence of HI titers (>= 1:10) was 27.1\% (95\% CI: 23.5-31.3) and 53.5\% (95\% CI: 50.9-56.2) compared to 1.7\% and 5.5\%, respectively, for pre-pandemic sera, accounting for a serologically determined incidence of influenza A (H1N1) 2009 during the season 2009/2010 of 25,4\% (95\% CI : 19.3-30.5) in children aged 1-4 years and 48.0\% (95\% CI: 42.6-52.0) in 5-17 year old children. Of children with HI titers >= 1: 10, 25.5\% (95\% CI: 22.5-28.8) reported no history of any infectious disease since June 2009. Among vaccinated children, 92\% (95\%-CI: 87.0-96.6) of the 5-17 year old but only 47.8\% (95\%-CI: 33.5-66.5) of the 1-4 year old children exhibited HI titers against influenza A virus (H1N1) 2009. Conclusion: Serologically determined incidence of influenza A (H1N1) 2009 infections in children indicates high infection rates with older children (5-17 years) infected twice as often as younger children. In about a quarter of the children with HI titers after the season 2009/2010 subclinical infections must be assumed. Low HI titers in young children after vaccination with the AS03(B)-adjuvanted split virion vaccine need further scrutiny.}, language = {en} } @article{HofmannBoettgerRangeetal.2017, author = {Hofmann, Sigrun Ruth and B{\"o}ttger, Fanny and Range, Ursula and L{\"u}ck, Christian and Morbach, Henner and Girschick, Hermann Joseph and Suttorp, Meinolf and Hedrich, Christian Michael}, title = {Serum interleukin-6 and CCL11/eotaxin may be suitable biomarkers for the diagnosis of chronic nonbacterial osteomyelitis}, series = {Frontiers in Pediatrics}, volume = {5}, journal = {Frontiers in Pediatrics}, doi = {10.3389/fped.2017.00256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172744}, year = {2017}, abstract = {Objectives: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO). Study design: Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses. Results: For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi-component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Iα, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses. Conclusion: Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted.}, language = {en} } @article{NeubauerMorbachSchwarzetal.2011, author = {Neubauer, Henning and Morbach, Henner and Schwarz, Tobias and Wirth, Clemens and Girschick, Hermann and Beer, Meinrad}, title = {Popliteal Cysts in Paediatric Patients: Clinical Characteristics and Imaging Features on Ultrasound and MRI}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68662}, year = {2011}, abstract = {Popliteal cysts, or Baker cysts, are considered rare in children and may exhibit particular features, as compared with adults. We studied data from80 paediatric patients with 55 Baker cysts, examined over a period of 7 years, and correlated clinical presentation with findings on ultrasonography and MRI. Prevalence of popliteal cysts was 57\% in arthritic knees, 58\% with hypermobility syndrome, and 28\% without risk factors. Only one patient had a trauma history and showed an ipsilateral cyst. Mean cyst volume was 3.4 mL; cysts were larger in boys. Patients with arthritis had echogenic cysts in 53\%. Cyst communication with the joint space was seen in 64\% on ultrasonography and 86\% on MRI. In conclusion, Baker cysts are a common finding in a clinically preselected paediatric population. Children with Baker cysts should be assessed for underlying arthritis and inherited joint hypermobility, while sporadic Baker cysts appear to be common, as well.}, subject = {Medizin}, language = {en} } @article{WiegeringSchickBeeretal.2011, author = {Wiegering, Verena and Schick, Judith and Beer, Meinrad and Gattenl{\"o}hner, Stefan and Girschick, Hermann and Liese, Johannes and Schlegel, Paul and Eyrich, Matthias}, title = {Varicella-zoster virus infections in immunocompromised patients - a single centre 6-years analysis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68723}, year = {2011}, abstract = {Background: Infection with varicella-zoster virus (VZV) contemporaneously with malignant disease or immunosuppression represents a particular challenge and requires individualized decisions and treatment. Although the increasing use of varicella-vaccines in the general population and rapid initiation of VZVimmunoglobulins and acyclovir in case of exposure has been beneficial for some patients, immunocompromised individuals are still at risk for unfavourable courses. Methods: In this single center, 6-year analysis we review incidence, hospitalization and complication rates of VZVinfections in our center and compare them to published data. Furthermore, we report three instructive cases. Results: Hospitalization rate of referred children with VZV-infections was 45\%, among these 17\% with malignancies and 9\% under immunosuppressive therapy. Rate of complications was not elevated in these two high-risk cohorts, but one ALL-patient died due to VZV-related complications. We report one 4-year old boy with initial diagnosis of acute lymphoblastic leukemia who showed a rapidly fatal outcome of his simultaneous varicella-infection, one 1.8-year old boy with an identical situation but a mild course of his disease, and an 8.5-year old boy with a steroiddependent nephrotic syndrome. This boy developed severe hepatic involvement during his varicella-infection but responded to immediate withdrawl of steroids and administration of acyclovir plus single-dose cidofovir after nonresponse to acyclovir after 48 h. Conclusion: Our data show that patients with malignant diseases or immunosuppressive therapy should be hospitalized and treated immediately with antiviral agents. Despite these measures the course of VZV-infections can be highly variable in these patients. We discuss aids to individual decision-making for these difficult situations.}, subject = {Varizellen-Virus}, language = {en} } @article{BeckMorbachBeeretal.2010, author = {Beck, Christine and Morbach, Henner and Beer, Meinrad and Stenzel, Martin and Tappe, Dennis and Gattenl{\"o}hner, Stefan and Hofmann, Ulrich and Raab, Peter and Girschick, Hermann J.}, title = {Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67792}, year = {2010}, abstract = {Introduction: Chronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported. Methods: Thirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome. Results: Naproxen treatment was highly effective in general, inducing a symptom-free status in 43\% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67\% of them were clinically silent. Conclusions: Most children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics.}, subject = {Mikrobiologie}, language = {en} } @article{HedrichHofmannPabliketal.2013, author = {Hedrich, Christian M. and Hofmann, Sigrun R. and Pablik, Jessica and Morbach, Henner and Girschick, Hermann J.}, title = {Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)}, series = {Pediatric Rheumatology}, volume = {11}, journal = {Pediatric Rheumatology}, number = {47}, issn = {1546-0096}, doi = {10.1186/1546-0096-11-47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125694}, year = {2013}, abstract = {Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.}, language = {en} } @article{EberhardtHaasGirschicketal.2015, author = {Eberhardt, Christiane S. and Haas, Johannes-Peter and Girschick, Hermann and Schwarz, Tobias and Morbach, Henner and R{\"o}sen-Wolff, Angela and Foell, Dirk and Dannecker, Guenther and Schepp, Carsten and Ganser, Gerd and Honke, Nora and Eggermann, Thomas and M{\"u}ller-Berghaus, Jan and Wagner, Norbert and Ohl, Kim and Tenbrock, Klaus}, title = {No association of IL-12p40 pro1.1 polymorphism with juvenile idiopathic arthritis}, series = {Pediatric Rheumatology}, volume = {13}, journal = {Pediatric Rheumatology}, number = {61}, doi = {10.1186/s12969-015-0059-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136281}, year = {2015}, abstract = {Background: IL-12p40 plays an important role in the activation of the T-cell lines like Th17 and Th1-cells. Theses cells are crucial in the pathogenesis of juvenile idiopathic arthritis. A polymorphism in its promoter region and the genotype IL12p40 pro1.1 leads to a higher production of IL-12p40. We studied whether there is a difference in the distribution of the genotype in patients with JIA and the healthy population. Methods: In 883 patients and 321 healthy controls the IL-12p40 promoter genotype was identified by ARMS-PCR. Results: There is no association of IL-12p40 pro polymorphism neither in patients with JIA compared to controls nor in subtypes of JIA compared to oligoarthritis. We found a non-significant tendency of a higher prevalence of the genotype pro1.1 in systemic arthritis (32.4 \%) and in rheumatoid factor negative polyarthritis (30.5 \%) and a lower pro1.1 genotype in persistent oligoarthritis (20.7 \%) and in enthesitis-related arthritis (17 \%). Likelihood of the occurrence of genotype IL12-p40 pro1.1 in patients with systemic arthritis (OR 1.722, CI 95 \% 1.344-2.615, p 0.0129) and RF-negative polyarthritis (OR 1.576, CI 95 \% 1.046-2.376, p 0.0367) compared to persistent oligoarthritis was significantly higher. This was also true for comparison of their homozygous genotypes IL-12p40 pro 1.1 and 2.2 in systemic arthritis (OR 1.779, CI 95 \% 1.045-3.029, p 0.0338). However, in Bonferroni correction for multiple hypothesis this was not significant. Conclusion: A tendency of a higher prevalence of the genotype IL-12p40 pro1.1 in systemic arthritis and in rheumatoid factor negative polyarthritis was observed but not significant. Further investigations should be done to clarify the role IL-12p40 in the different subtypes of JIA.}, language = {en} } @article{HedrichHofmannPabliketal.2013, author = {Hedrich, Christian M. and Hofmann, Sigrun R. and Pablik, Jessica and Morbach, Henner and Girschick, Hermann J.}, title = {Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)}, series = {Pediatric Rheumatology}, volume = {11}, journal = {Pediatric Rheumatology}, number = {47}, doi = {10.1186/1546-0096-11-47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132456}, year = {2013}, abstract = {Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear. Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.}, language = {en} } @article{NeubauerEvangelistaMorbachetal.2012, author = {Neubauer, Henning and Evangelista, Laura and Morbach, Henner and Girschick, Hermann and Prelog, Martina and K{\"o}stler, Herbert and Hahn, Dietbert and Beer, Meinrad}, title = {Diffusion-weighted MRI of bone marrow oedema, soft tissue oedema and synovitis in paediatric patients: feasibility and initial experience}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75521}, year = {2012}, abstract = {Background: MRI has become the mainstay of diagnostic imaging in paediatric rheumatology for lesion detection, differential diagnosis and therapy surveillance. MR imaging of synovitis, in particular, is indispensable for early diagnosis and follow-up in arthritis patients. We used diffusion-weighted MRI (DWI) as a new imaging modality in comparison to standard MRI sequences to study bone marrow oedema, soft-tissue oedema and synovitis in paediatric patients. Methods: A total of 52 patients (mean age 11 ± 5 years) with bone marrow oedema (n = 31), soft-tissue oedema (n = 20) and synovitis (n = 15) were examined with transversal diffusion-weighted single-shot echoplanar imaging in addition to standard MR sequences (T2W TIRM, T1W pre- and post-contrast). Diffusion-weighted images were used for lesion detection and apparent diffusion coefficient (ADC, unit × 10-3 mm2/s) values were measured with ROI technique on ADC maps. Results: In 50 of 52 patients, DWI delineated the lesion of interest corresponding to pathological signal increase on standard sequences. Mean ADC was 1.60 ± 0.14 (range 1.38 - 1.99) in osseous lesions, 1.72 ± 0.31 (range 1.43 - 2.56) in soft tissue oedema and 2.82 ± 0.24 (range 2.47 - 3.18) for joint effusion (ANOVA p<0.001). No significant difference in mean ADC was seen for inflammatory vs. non-inflammatory lesions. Relative signal intensity of oedema was similar for DWI and T2W TIRM. DWI visualised synovial restricted diffusion with a mean ADC of 2.12 ± 0.45 in 12 of 15 patients with synovitis. Conclusions: Diffusion-weighted MRI reliably visualises osseous and soft tissue oedema, as compared to standard sequences. DWI of synovitis is feasible in large joints and presents a novel approach to contrast-free imaging of synovitis. Whole-body DWI for chronic non-bacterial osteomyelitis should be evaluated in future studies.}, subject = {Medizin}, language = {en} } @article{VogtGirschickSchweitzeretal.2020, author = {Vogt, Marius and Girschick, Hermann and Schweitzer, Tilmann and Benoit, Clemens and Holl-Wieden, Annette and Seefried, Lothar and Jakob, Franz and Hofmann, Christine}, title = {Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children}, series = {Orphanet Journal of Rare Diseases}, volume = {15}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-020-01500-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230505}, year = {2020}, abstract = {Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children's Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8\%) perinatal, 17 (34\%) infantile and 29 (58\%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88\%), low alkaline phosphatase (AP) activity (in 96\%), accumulating substrates of AP (in 58\%) and X-ray findings (in 48\%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78\%), impairment of mineralization (72\%), premature loss of teeth (64\%), musculoskeletal pain and craniosynostosis (each 64\%) and failure to thrive (62\%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.}, language = {en} } @article{DirksFischerHaaseetal.2021, author = {Dirks, Johannes and Fischer, Jonas and Haase, Gabriele and Holl-Wieden, Annette and Hofmann, Christine and Girschick, Hermann and Morbach, Henner}, title = {CD21\(^{lo/-}\)CD27\(^-\)IgM\(^-\) Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis}, series = {Frontiers in Pediatrics}, volume = {9}, journal = {Frontiers in Pediatrics}, issn = {2296-2360}, doi = {10.3389/fped.2021.635815}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236286}, year = {2021}, abstract = {Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism in these patients. Additionally, ANAs were considered potential biomarkers encompassing a clinically homogenous subgroup of JIA patients. However, in ANA+ JIA patients, the site of dysregulated B cell activation as well as the B cell subsets involved in this process is still unknown. Hence, in this cross-sectional study, we aimed in an explorative approach at characterizing potential divergences in B cell differentiation in ANA+ JIA patients by assessing the distribution of peripheral blood (PB) and synovial fluid (SF) B cell subpopulations using flow cytometry. The frequency of transitional as well as switched-memory B cells was higher in PB of JIA patients than in healthy controls. There were no differences in the distribution of B cell subsets between ANA- and ANA+ patients in PB. However, the composition of SF B cells was different between ANA- and ANA+ patients with increased frequencies of CD21\(^{lo/-}\)CD27\(^-\)IgM\(^-\) "double negative" (DN) B cells in the latter. DN B cells might be a characteristic subset expanding in the joints of ANA+ JIA patients and are potentially involved in the antinuclear immune response in these patients. The results of our explorative study might foster further research dissecting the pathogenesis of ANA+ JIA patients.}, language = {en} } @article{HedrichMorbachReiseretal.2020, author = {Hedrich, Christian M. and Morbach, Henner and Reiser, Christiane and Girschick, Hermann J.}, title = {New Insights into Adult and Paediatric Chronic Non-bacterial Osteomyelitis CNO}, series = {Current Rheumatology Reports}, volume = {22}, journal = {Current Rheumatology Reports}, issn = {1523-3774}, doi = {10.1007/s11926-020-00928-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232636}, year = {2020}, abstract = {Purpose of Review To describe in detail the clinical synopsis and pathophysiology of chronic non-bacterial osteomyelitis and SAPHO syndrome. Recent Findings Chronic non-bacterial osteomyelitis (CNO) has been identified as a disease entity for almost 50 years. This inflammatory bone disorder is characterized by osteolytic as well as hyperostotic/osteosclerotic lesions. It is chronic in nature, but it can present with episodic flairs and phases of remission, which have led to the denomination "chronic recurrent osteomyelitis", with its severe multifocal form "chronic recurrent multifocal osteomyelitis" (CRMO). For almost three decades, an infectious aetiology had been considered, since especially Propionibacterium acnes had been isolated from bone lesions of individual patients. However, this concept has been challenged since long-term antibiotic therapy did not alter the course of disease and modern microbiological techniques (including PCR) failed to confirm bone infection as an underlying cause. Over recent years, a profound dysregulation of cytokine expression profiles has been demonstrated in innate immune cells of CNO patients. A hallmark of monocytes from CNO patients is the failure to produce immune regulatory cytokines interleukin-10 (IL-10) and IL-19, which have been linked with genetic and epigenetic alterations. Subsequently, a significant upregulation of pro-inflammatory, NLRP3 inflammasome-dependent cytokines (IL-1β and TNF-α), has been demonstrated. Summary The current knowledge on CNO, the underlying molecular pathophysiology, and modern imaging strategies are summarized; differential diagnoses, treatment options, outcome measures, as well as quality of life studies are discussed.}, language = {en} } @article{FischerDirksKlaussneretal.2022, author = {Fischer, Jonas and Dirks, Johannes and Klaussner, Julia and Haase, Gabriele and Holl-Wieden, Annette and Hofmann, Christine and Hackenberg, Stephan and Girschick, Hermann and Morbach, Henner}, title = {Effect of clonally expanded PD-1\(^h\)\(^i\)\(^g\)\(^h\) CXCR5-CD4+ peripheral T Helper cells on B cell differentiation in the joints of patients with antinuclear antibody-positive juvenile idiopathic arthritis}, series = {Arthritis \& Rheumatology}, volume = {74}, journal = {Arthritis \& Rheumatology}, number = {1}, doi = {10.1002/art.41913}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256607}, pages = {150-162}, year = {2022}, abstract = {Objective Antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA. Methods Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1\(^h\)\(^i\)\(^g\)\(^h\)CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next-generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro. Results Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)-coexpressing PD-1\(^h\)\(^i\)\(^g\)\(^h\)CXCR5-HLA-DR+CD4+ T cells that accumulate in the joints of ANA-positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T-bet and B lymphocyte-induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL-21 and IFNy, skewed B cell differentiation toward a CD21\(^l\)\(^o\)\(^w\)\(^/\)\(^-\)CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21\(^l\)\(^o\)\(^w\)\(^/\)\(^-\)CD11c+CD27-IgM- double-negative (DN) B cells in situ.}, language = {en} } @article{GirschickWolfMorbachetal.2015, author = {Girschick, Hermann and Wolf, Christine and Morbach, Henner and Hertzberg, Christoph and Lee-Kirsch, Min Ae}, title = {Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene}, series = {Pediatric Rheumatology}, volume = {13}, journal = {Pediatric Rheumatology}, number = {37}, doi = {10.1186/s12969-015-0035-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149990}, year = {2015}, abstract = {Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia.}, language = {en} } @article{DirksHaaseCantaertetal.2022, author = {Dirks, Johannes and Haase, Gabriele and Cantaert, Tineke and Frey, Lea and Klaas, Moritz and Rickert, Christian H. and Girschick, Hermann and Meffre, Eric and Morbach, Henner}, title = {A novel AICDA splice-site mutation in two siblings with HIGM2 permits somatic hypermutation but abrogates mutational targeting}, series = {Journal of Clinical Immunology}, volume = {42}, journal = {Journal of Clinical Immunology}, number = {4}, doi = {10.1007/s10875-022-01233-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324253}, pages = {771-782}, year = {2022}, abstract = {Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.}, language = {en} } @article{NentwichRufGirschicketal.2019, author = {Nentwich, Julia and Ruf, Katharina and Girschick, Hermann and Holl-Wieden, Annette and Morbach, Henner and Hebestreit, Helge and Hofmann, Christine}, title = {Physical activity and health-related quality of life in chronic non-bacterial osteomyelitis}, series = {Pediatric Rheumatology}, volume = {17}, journal = {Pediatric Rheumatology}, doi = {10.1186/s12969-019-0351-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323710}, year = {2019}, abstract = {Background Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC). Methods 15 patients with CNO and 15 age and gender matched HC aged 13-18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior. Results At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL. Conclusion Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity.}, language = {en} }