Publications by authors named "Claas H Hinze"

19 Publications

  • Page 1 of 1

A dysregulated interleukin-18/interferon-γ/CXCL9 axis impacts treatment response to canakinumab in systemic juvenile idiopathic arthritis.

Rheumatology (Oxford) 2021 Feb 10. Epub 2021 Feb 10.

Department of Pediatric Rheumatology and Immunology, University Hospital Muenster, Muenster, Germany.

Objectives: The monoclonal interleukin-1beta (IL-1β) antibody canakinumab is approved for the treatment of systemic juvenile idiopathic arthritis (SJIA). Its efficacy has been proven in several trials, but not all patients show a complete and sustained response to therapy. We aimed to analyze the association of baseline serum biomarkers with treatment outcome in patients with SJIA treated with canakinumab.

Methods: Serum samples from 54 patients with active SJIA without recent macrophage activation syndrome (MAS) treated with canakinumab in an open-label response characterization study were subjected to a multiplexed bead array assay. Interesting targets from these analyses were validated by ELISA. Clinical treatment outcomes included modified pediatric American College of Rheumatology (pACR) 30 and 90 responses, clinically inactive disease (CID) within 15 days of treatment, and sustained complete response, defined as pACR100 or CID within 15 days of treatment plus no future flare or MAS.

Results: In canakinumab naïve patients most biomarkers were elevated when compared with healthy controls at baseline and some rapidly decreased by day 15 (IL-1RA, IL-6, IL-18 and S100A12). Responders had higher IL-18 and IFN-γ levels and lower CXCL9 levels at baseline, emphasized by the IL-18: CXCL9 and IFN-γ:CXCL9 ratios. These ratios had significant accuracy in predicting treatment responses.

Conclusion: Differential regulation of the IL-18/IFN-γ/CXCL9 axis is observed in patients with SJIA. Higher IL-18: CXCL9 and IFN-γ:CXCL9 ratios at baseline are associated with a better clinical response to canakinumab treatment in SJIA. Future studies are needed to validate these findings and determine their generalizability to patients with recent MAS.
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http://dx.doi.org/10.1093/rheumatology/keab113DOI Listing
February 2021

Reply.

Arthritis Rheumatol 2019 11 25;71(11):1969-1970. Epub 2019 Sep 25.

University Hospital Münster, Münster, Germany.

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http://dx.doi.org/10.1002/art.41021DOI Listing
November 2019

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

Arthritis Rheumatol 2019 03 24;71(3):451-459. Epub 2019 Jan 24.

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Objective: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA).

Methods: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal.

Results: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36).

Conclusion: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.
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http://dx.doi.org/10.1002/art.40727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393224PMC
March 2019

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

J Clin Invest 2018 08 6;128(9):3957-3975. Epub 2018 Aug 6.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.
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http://dx.doi.org/10.1172/JCI97116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118590PMC
August 2018

Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria.

Pediatr Rheumatol Online J 2018 Jun 25;16(1):40. Epub 2018 Jun 25.

German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen Department of Dermatology, Oberammergau Center for Rheumatic Diseases, Oberammergau, Germany.

Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.

Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.

Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.

Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
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http://dx.doi.org/10.1186/s12969-018-0257-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019723PMC
June 2018

Current management of juvenile dermatomyositis in Germany and Austria: an online survey of pediatric rheumatologists and pediatric neurologists.

Pediatr Rheumatol Online J 2018 Jun 20;16(1):38. Epub 2018 Jun 20.

German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.

Background: Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease with broad variations of the individual course. Data on the optimal management are mostly lacking. Currently treatment decisions are often based on experts' opinions. In order to develop consensus-based treatment strategies for JDM in Germany a survey was pursued to analyze the current clinical practice.

Methods: An online survey addressing all members of the Society for Pediatric Rheumatology (GKJR) in Germany and Austria and pediatric neurologists with expertise in JDM was performed in February/March of 2016. The questionnaire consisted of 5 case scenarios including diagnostic criteria, treatment of moderate, severe and refractory JDM, using either multiple choice or a 5-point Likert scale. Basic descriptive statistics were used to analyze the findings.

Results: The survey was completed by 60 pediatric rheumatologists and 7 pediatric neurologists experienced in the management of JDM. Typical findings allowing a diagnosis were considered to be: typical skin changes, proximal muscle weakness, MRI findings, elevated muscle enzymes, nailfold capillary changes, presence of calcinosis and muscle biopsy. Regarding induction treatment of moderate/severe JDM: 59%/74% opted for intermittent intravenous methylprednisolone (IVMP) pulse therapy, and 21%/40% for conventional high-dose oral glucocorticoids. Methotrexate (MTX) was the preferred disease-modifying conventional anti-rheumatic drug (cDMARD) for moderate and severe JDM. Regarding the management of refractory moderate or severe JDM, intravenous immune globulins, mycophenolate mofetil and rituximab were preferred treatment options.

Conclusion: There is consensus about the diagnosis of JDM strongly supported by classic clinical and MRI findings. There is great variety in the treatment of JDM in Germany regarding both induction and maintenance therapy. The development of consensus-based treatment strategies for JDM based on harmonization of current clinical practice is essential in order to allow comparative effectiveness research in the future.
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http://dx.doi.org/10.1186/s12969-018-0256-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011340PMC
June 2018

Varicella-zoster-virus vaccination in immunosuppressed children with rheumatic diseases using a pre-vaccination check list.

Pediatr Rheumatol Online J 2018 Mar 2;16(1):15. Epub 2018 Mar 2.

German Center for Pediatric and Adolescent Rheumatology, Gehfeldstr. 24, 82467, Garmisch-Partenkirchen, Germany.

Background: The goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization.

Methods: This prospective study included seronegative patients (VZV-IgG ≤200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count ≥3000/mm, lymphocytes ≥1200/mm, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count ≥200/mm and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored.

Results: Twenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV-IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare.

Conclusions: VZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications.

Trial Registration Number: ISRCRTN trial registration number 21654693 , date of registration February 12, 2018, retrospectively registered.
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http://dx.doi.org/10.1186/s12969-018-0231-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833060PMC
March 2018

Practice and consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis in Germany.

Pediatr Rheumatol Online J 2018 Jan 22;16(1). Epub 2018 Jan 22.

Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Albert-Schweitzer-Campus 1, Building W30, 48149, Münster, Germany.

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 harmonize diagnostic and therapeutic approaches in Germany.

Methods: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements.

Results: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy.

Conclusions: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.
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http://dx.doi.org/10.1186/s12969-018-0224-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778670PMC
January 2018

Challenges of Diagnosing Cognitive Dysfunction With Neuropsychiatric Systemic Lupus Erythematosus in Childhood.

Arthritis Care Res (Hoboken) 2017 10 29;69(10):1449-1459. Epub 2017 Aug 29.

Cincinnati Children's Hospital and University of Cincinnati College of Medicine, Cincinnati, Ohio.

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http://dx.doi.org/10.1002/acr.23163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476521PMC
October 2017

Treatment with high-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins in patients with juvenile dermatomyositis who are intolerant to intravenous immune globulins: a report of 5 cases.

Pediatr Rheumatol Online J 2016 Sep 13;14(1):52. Epub 2016 Sep 13.

Klinik für Pädiatrische Rheumatologie und Immunologie, Universitätsklinikum Münster, Münster, Germany.

Background: High-dose intravenous immune globulins (IVIg) are frequently used in refractory juvenile dermatomyositis (JDM) but are often poorly tolerated. High-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins (fSCIg) allow the administration of much higher doses of immune globulins than conventional subcutaneous immune globulin therapy and may be an alternative to IVIg. The safety and efficacy of fSCIg therapy in JDM is unknown.

Case Presentation: In this retrospective case series, five patients with steroid-refractory severe JDM were treated with high-dose fSCIg due to IVIg adverse effects (severe headaches, nausea, vomiting, difficult venous access). Peak serum IgG levels, muscle enzymes, the childhood myositis assessment scale and adverse effects were retrieved for at least 6 months following intiation of fSCIg. Data were analyzed by descriptive statistics. Patients initially received fSCIg 1 g/kg every 14 days, resulting in median IgG peak levels of 1901 mg/dl (1606-2719 mg/dl), compared to median IgG peak and trough levels while previously receiving IVIg of 2741 mg/dl (2429-2849 mg/dl) and 1351 mg/dl (1156-1710 mg/dl). Additional antirheumatic therapies consisted of low-dose glucocorticoid therapy, methotrexate, mycophenolate mofetil and/or rituximab. Two patients maintained clinically inactive disease and three patients had only a partial treatment response. In the three patients with partial treatment response, fSCIg 1 g/kg was then given on days 1 and 6 of every 28-day cycle resulting in IgG peak levels of between 2300-2846 mg/dl (previously 1606-1901 mg/dl on the biweekly regimen), resulting in clinically inactive disease in two of the three patients. There were no relevant adverse effects that limited continuation of fSCIg treatment.

Conclusions: High-dose fSCIg is well-tolerated in patients with JDM and high peak serum IgG levels can be achieved which may be important for treatment success. High-dose fSCIg may therefore be an alternative to high-dose IVIg and deserves further study.

Trial Registration: This is a case series and data were retrospectively registered.
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http://dx.doi.org/10.1186/s12969-016-0112-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022227PMC
September 2016

Leukocyte adhesion deficiency type 1 presenting with recurrent pyoderma gangrenosum and flaccid scarring.

Pediatr Dermatol 2010 Sep-Oct;27(5):500-3. Epub 2010 Aug 27.

Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.

We report an 11-year-old boy with a longstanding history of recurrent pyoderma gangrenosum and abnormal wound healing who eventually developed a fatal invasive fungal infection. This article emphasizes the importance to consider leukocyte adhesion deficiency type 1 in the differential diagnosis of patients with recurrent skin ulcers.
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http://dx.doi.org/10.1111/j.1525-1470.2010.01260.xDOI Listing
April 2011

Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis.

Arthritis Res Ther 2010 24;12(3):R123. Epub 2010 Jun 24.

Division of Rheumatology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.

Introduction: Previous observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene-expression signature. The aim of this study was to determine the association of this signature with peripheral blood mononuclear cell (PBMC) subpopulations and its specificity for sJIA as compared with related conditions.

Methods: The 199 patients with JIA (23 sJIA and 176 non-sJIA) and 38 controls were studied. PBMCs were isolated and analyzed for multiple surface antigens with flow cytometry and for gene-expression profiles. The proportions of different PBMC subpopulations were compared among sJIA, non-sJIA patients, and controls and subsequently correlated with the strength of the erythropoiesis signature. Additional gene-expression data from patients with familial hemophagocytic lymphohistiocytosis (FHLH) and from a published sJIA cohort were analyzed to determine whether the erythropoiesis signature was present.

Results: Patients with sJIA had significantly increased proportions of immature cell populations, including CD34+ cells, correlating highly with the strength of the erythropoiesis signature. The erythropoiesis signature strongly overlapped with the gene-expression pattern in purified immature erythroid precursors. The expansion of immature cells was most prominently seen in patients with sJIA and anemia, even in the absence of reticulocytosis. Patients with non-sJIA and anemia did not exhibit the erythropoiesis signature. The erythropoiesis signature was found to be prominent in patients with FHLH and in a published cohort of patients with active sJIA, but not in patients with inactive sJIA.

Conclusions: An erythropoiesis signature in active sJIA is associated with the expansion of CD34+ cells, also is seen in some patients with FHLH and infection, and may be an indicator of ineffective erythropoiesis and hemophagocytosis due to hypercytokinemia.
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http://dx.doi.org/10.1186/ar3061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911917PMC
November 2010

Kawasaki disease without fever.

Pediatr Infect Dis J 2009 Oct;28(10):927-8

Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Kawasaki disease (KD) characteristically presents with prolonged, remittent fever in addition to other clinical findings. We report the case of a 3-month-old boy who developed characteristic manifestations of KD and coronary aneurysms in the absence of fever. This case report underlines the difficulty to diagnose KD in young infants.
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http://dx.doi.org/10.1097/INF.0b013e3181a81cf0DOI Listing
October 2009

Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity.

Arthritis Rheum 2009 Sep;60(9):2772-81

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Objective: To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE).

Methods: One hundred eleven patients with childhood-onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physician's assessment of global disease activity. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved, or worsening). Plasma and urinary NGAL levels were measured by enzyme-linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed-effect models.

Results: Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score.

Conclusion: Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity.
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http://dx.doi.org/10.1002/art.24751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064260PMC
September 2009

Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis.

Arthritis Rheum 2009 Jul;60(7):2102-12

Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Objective: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents.

Methods: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0).

Results: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well.

Conclusion: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.
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http://dx.doi.org/10.1002/art.24601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782469PMC
July 2009

Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.

Arthritis Rheum 2009 Jul;60(7):2113-23

William S. Rowe Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Objective: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures.

Methods: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization.

Results: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets.

Conclusion: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.
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http://dx.doi.org/10.1002/art.24534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741130PMC
July 2009

Rituximab therapy for severe refractory chronic Henoch-Schönlein purpura.

J Pediatr 2009 Jul;155(1):136-9

University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.

To report on the efficacy of rituximab (RTX) therapy in standard treatment-refractory, chronic Henoch-Schönlein purpura, a retrospective chart review of 3 pediatric patients treated with RTX for severe refractory chronic Henoch-Schönlein purpura was performed. All 3 patients responded to 1 or 2 courses of RTX without serious adverse events.
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http://dx.doi.org/10.1016/j.jpeds.2008.12.049DOI Listing
July 2009

B-cell depletion in Wegener's granulomatosis.

Clin Rev Allergy Immunol 2008 Jun;34(3):372-9

Division of Rheumatology-ML-4010, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.

Wegener's granulomatosis (WG) is a chronic, relapsing, systemic necrotizing vasculitis with typical pathologic findings of granulomatous inflammation and pauci-immune vasculitis. Untreated, the condition has a very high mortality, and contemporary treatment strategies carry a high risk of treatment-related morbidity. Antineutrophil cytoplasmic antibodies (ANCA) play a central role in the pathogenesis of the disease. It is unclear how ANCA develop, but B cells are of major importance in the disease pathogenesis as precursors of ANCA-producing plasma cells and, possibly, also as antigen-presenting and cytokine-producing cells. Therefore, the use of B-cell depletion therapy, e.g., with rituximab appears to be an attractive treatment option in WG. Several small clinical trials and case reports show promising results with a high rate of clinical remissions achieved in patients that were refractory to or intolerant of conventional treatment regimens. However, granulomatous manifestations seemed to be less responsive to B-cell depletion therapy. B-cell depletion therapy was generally well tolerated. A large prospective, randomized, double-blind clinical trial evaluating the efficacy of B-cell depletion therapy in WG is pending.
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http://dx.doi.org/10.1007/s12016-007-8057-7DOI Listing
June 2008

B cell depletion: on the rise.

J Pediatr 2007 Apr;150(4):335-7

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http://dx.doi.org/10.1016/j.jpeds.2006.12.050DOI Listing
April 2007