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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.
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.
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.
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.
Analyse der Immunglobulinrepertoire-Veränderungen in B Zellen von Kindern mit Autoimmunerkrankungen
(2006)
B Zellen sind die zellulären Träger einer gegen Infektionserreger gerichteten, humoralen und protektiven Immunität. In der Entstehung von Autoimmunerkrankungen und in der Aufrechterhaltung von chronischen Entzündungen scheint diesen Zellen eine entscheidende Rolle zuzukommen. In dieser Arbeit wurden in B Zellen von Patienten mit rheumatischen Erkrankungen molekulare Mechanismen untersucht, die es der B Zelle außerhalb des Knochenmarkes erlauben, ihre Rezeptorspezifität zu verändern. Ein solcher Vorgang könnte Verschiebungen des Immunglobulinrepertoires in Richtung Autoreaktivität erklären.
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.
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.
Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000+2T -> G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage.
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.
Immunization of preterm infants: current evidence and future strategies to individualized approaches
(2022)
Preterm infants are at particularly high risk for infectious diseases. As this vulnerability extends beyond the neonatal period into childhood and adolescence, preterm infants benefit greatly from infection-preventive measures such as immunizations. However, there is an ongoing discussion about vaccine safety and efficacy due to preterm infants’ distinct immunological features. A significant proportion of infants remains un- or under-immunized when discharged from primary hospital stay. Educating health care professionals and parents, promoting maternal immunization and evaluating the potential of new vaccination tools are important means to reduce the overall burden from infectious diseases in preterm infants. In this narrative review, we summarize the current knowledge about vaccinations in premature infants. We discuss the specificities of early life immunity and memory function, including the role of polyreactive B cells, restricted B cell receptor diversity and heterologous immunity mediated by a cross-reactive T cell repertoire. Recently, mechanistic studies indicated that tissue-resident memory (Trm) cell populations including T cells, B cells and macrophages are already established in the fetus. Their role in human early life immunity, however, is not yet understood. Tissue-resident memory T cells, for example, are diminished in airway tissues in neonates as compared to older children or adults. Hence, the ability to make specific recall responses after secondary infectious stimulus is hampered, a phenomenon that is transcriptionally regulated by enhanced expression of T-bet. Furthermore, the microbiome establishment is a dominant factor to shape resident immunity at mucosal surfaces, but it is often disturbed in the context of preterm birth. The proposed function of Trm T cells to remember benign interactions with the microbiome might therefore be reduced which would contribute to an increased risk for sustained inflammation. An improved understanding of Trm interactions may determine novel targets of vaccination, e.g., modulation of T-bet responses and facilitate more individualized approaches to protect preterm babies in the future.