[Arthritis and osteomyelitis in childhood and adolescence-Bacterial and nonbacterial]. / Arthritis und Osteomyelitis im Kindes- und Jugendalter ­ bakteriell und nichtbakteriell.

Bacterial arthritis and osteomyelitis are usually acute diseases, which in this way differ from the often insidious course of nonbacterial osteomyelitis; however, there is often an overlap both in less acute courses of bacterial illnesses and also in nonbacterial osteitis. The overlapping clinical phenomena can be explained by similar pathophysiological processes. In bacteria-related illnesses the identification of the pathogen and empirical or targeted anti-infectious treatment are prioritized, whereas no triggering agent is known for nonbacterial diseases. The diagnostics are based on the exclusion of differential diagnoses, clinical scores and magnetic resonance imaging (MRI). An activity-adapted anti-inflammatory treatment is indicated.

Priorities in Chronic nonbacterial osteomyelitis (CNO) - results from an international survey and roundtable discussions.

OBJECTIVE: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that predominantly affects children and young people. The pathophysiology and molecular mechanisms of CNO remain poorly understood, and diagnostic criteria and biomarkers are lacking. As a result, treatment is empiric and follows personal experience, case series and expert consensus plans. METHODS: A survey was designed to gain insight on clinician and patient experiences of diagnosing and treating CNO and to collate opinions on research priorities. A version containing 24 questions was circulated among international expert clinicians and clinical academics (27 contacted, 21 responses). An equivalent questionnaire containing 20 questions was shared to explore the experience and priorities of CNO patients and family members (93 responses). RESULTS: Responses were used to select topics for four moderated roundtable discussions at the "International Conference on CNO and autoinflammatory bone disease" (Liverpool, United Kingdom, May 25-26th, 2022). The group identified deciphering the pathophysiology of CNO to be the highest priority, followed by clinical trials, necessary outcome measures and classification criteria. Surprisingly, mental wellbeing scored behind these items. CONCLUSIONS: Agreement exists among clinicians, academics, patients and families that deciphering the pathophysiology of CNO is of highest priority to inform clinical trials that will allow for the approval of medications for the treatment of CNO by regulatory agencies.

Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.

Treatment of type I ROP with intravitreal bevacizumab or laser photocoagulation according to retinal zone.

AIMS: To investigate the outcome of intravitreal bevacizumab (IVB) compared with laser photocoagulation in type I retinopathy of prematurity (ROP). METHODS: Case records of 54 consecutive very low birth weight (VLBW) infants with type I ROP (posterior ROP, n=33; peripheral zone II, n=21) who were treated either with IVB (n=37) or laser photocoagulation (n=17) between 2011 and 2015 were retrospectively evaluated. RESULTS: Patients with posterior ROP displayed significantly faster regression of active ROP within 12 days (range 9-15 days) if treated with IVB compared with laser photocoagulation, where active ROP regressed within 57 days (range 28-63 days) (p>0.001). No difference was observed in peripheral zone II.Five of seven patients (12%) who developed a recurrence in both eyes after IVB required additional laser photocoagulation within a mean of 12.7 weeks (11.3-15.6 weeks) after the previous treatment. After laser photocoagulation one patient with posterior ROP developed macular dragging and another patient developed a temporary exudative retinal detachment in both eyes. 12 months after treatment the spherical equivalent was not statistically significant different between IVB and laser photocoagulation in posterior ROP patients. However, IVB lead to a significant lower spherical equivalent in infants with posterior ROP (+0.37 dioptres, range -0.5 to +1.88 dioptres) compared with peripheral zone II (+3.0 dioptres range +2.0 to +4.0 dioptres, p<0.001). CONCLUSIONS: IVB leads to faster regression of active ROP in infants with posterior ROP compared with laser photocoagulation. Spherical equivalent after 12 months was comparable in those treated with IVB and laser photocoagulation, but it was significantly lower in posterior ROP than in peripheral zone II.

Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1ß expression and release.

Chronic recurrent multifocal osteomyelitis (CRMO) is characterized by reduced activation of protein kinases ERK1 and 2 in monocytes resulting in impaired IL-10 expression. IL10 and its homologs IL19 and IL20 are organized in the IL10 cluster on chromosome 1q32. IL-10 and IL-19 are immune-regulatory cytokines, while IL-20 acts in a pro-inflammatory manner. The NLRP3 inflammasome, a multi-protein complex forming in response to innate stimuli, mediates IL-1ß cleavage and release. Here, we investigated IL-10-related cytokine expression in CRMO monocytes, underlying molecular events, and effects on inflammatory responses. We observed reduced anti-inflammatory IL-10 and IL-19 expression, and enhanced IL-20 expression in CRMO monocytes. Reduced IL-10 and IL-19 expression was associated with impaired Sp-1 recruitment to regulatory regions, contributing to NLRP3 inflammasome activation, which may induce inflammatory bone-loss. Our findings underscore the importance of balanced receptor-, cell-, and tissue-specific cytokine expression for immune homeostasis, providing additional arguments for cytokine blocking strategies in CRMO.

CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA. METHODS: A genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before. RESULTS: SNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (p<0.05), strengthening the evidence for involvement of these genes in JIA. In the majority of these replicated SNPs, effect sizes were larger when analysing a homogeneous patient cohort than when analysing all subtypes. We identified two novel associations with oligoarticular and RF-negative polyarticular JIA: CD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively). CONCLUSIONS: The CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

Genetic variation in VTCN1 (B7-H4) is associated with course of disease in juvenile idiopathic arthritis.

OBJECTIVE: The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. METHODS: Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2 years. RESULTS: Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10(-5)) and three SNPs; VTCN1 rs10 923 223 (p=4.4*10(-5)), VTCN1 rs12 046 117 (p=0.017) and CDK6 rs42 041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10 923 223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. CONCLUSIONS: This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease.

[B-cell targeted therapy for children and adolescents with rheumatic diseases]. / B-Zell-gerichtete Therapien bei Kindern und Jugendlichen mit rheumatischen Erkrankungen.

The introduction of cytokine-targeted therapies has significantly improved the treatment options of rheumatic diseases; however, some patients are also refractory to these treatment measures. The B cells play a central role in the pathogenesis of many rheumatic diseases and B-cell targeted therapies are a promising option as second-line medication for treating patients with a refractory disease course. Randomized controlled trials analyzing the efficacy of B-cell directed therapies for childhood rheumatic diseases have not yet been performed. The use of the B-cell depleting antibody rituximab showed positive results in non-controlled case series of juvenile systemic lupus erythematosus (SLE) patients. Patients with a refractory disease course of oligoarticular or polyarticular juvenile idiopathic arthritis might also benefit from B-cell depletion using rituximab. The B cell-targeting therapies for the treatment of childhood rheumatic diseases should be initiated and closely supervised by a pediatric rheumatologist.

Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression.

Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced (p<0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.

Whole-body MRI in the childhood form of hypophosphatasia.

Hypophosphatasia (HPP) is a rare inborn error of bone metabolism caused by various defects in the gene coding for the tissue-nonspecific alkaline phosphatase (TNSAP). It results in a reduced activity of the TNSAP and elevated concentrations of its substrates, including inorganic pyrophosphate. Clinical features of HPP include defective bone mineralisation with bone deformities, fractures and chronic non-bacterial osteomyelitis. Renal damage due to calcification, craniosynostosis and dental abnormalities with premature loss of dentition are further complications. Until now, detailed descriptions of whole-body magnetic resonance imaging (WB-MRI) in HPP do not exist. Here, we analysed WB-MRIs of 4 children with the childhood form of HPP. Deformities and defects of the long bones could be seen. All patients showed radiological lesions in the metaphyses of the long bones predominantly in the lower extremities being consistent with hyperaemia and oedema. Differential diagnosis includes an inflammatory process being active in these locations.

Reference values for B cell subpopulations from infancy to adulthood.

The composition of the peripheral blood lymphocyte compartment underlies developmental changes during ontogeny. Recently, several new B cell populations have been characterized which were suggested to develop in an age-dependent manner. However, age-dependent reference values for distinct B cell populations have rarely been reported. Therefore, we have characterized developmental changes in peripheral B cell populations from infancy to adulthood in order to define age-dependent reference values. Using a flow cytometric approach we analysed the frequencies as well as the absolute counts of naive, switched and non-switched memory B cells, CD27-negative memory B cells, transitional B cells as well as CD21(low) CD38(low) B cells from neonates up to the age of 50 years. Most of the B cell subsets showed age-dependent developmental changes: while the peripheral B cell pool during infancy is characterized predominantly by transitional and naive B cells, the fraction of switched and non-switched memory B cells increases gradually with age. CD21(low) CD38(low) B cells as well as plasmablasts do not exhibit developmental changes. In summary, we could demonstrate particular changes in the peripheral blood B cell compartment during ontogeny. This study provides reference values of different B cell subpopulations offering comparability for studies addressing disturbed peripheral B cell development in immunodeficiency, autoimmunity or B cell reconstitution following cell-depleting therapies.

[Steroid-induced spinal epidural lipomatosis in pediatric patients]. / Kortikosteroid-induzierte spinale epidurale Lipomatose bei pädiatrischen Patienten.

We describe three adolescent patients with chronic autoimmune disorders who developed back pain and, in two cases, spinal symptoms several months after initiating chronic treatment with glucocorticoids. In all cases, MRI showed extensive spinal epidural lipomatosis, a rare but classic untoward effect of chronic glucocorticoid therapy. Analysis of these three, as well as 11 other pediatric cases extracted from the international literature, revealed that spinal epidural lipomatosis manifests most commonly with back pain and within a mean of 1.3 years (range, 3 month-6.5 years) after initiation of therapy with corticosteroids. It frequently remits after reduction of the corticosteroid dose.

Clinical course and prognostic value of disease activity in the first two years in different subtypes of juvenile idiopathic arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease involving chronic arthritis. The clinical course is characterized by a fluctuating pattern of active and inactive disease. We have described in detail the clinical course in different JIA subtypes during the first 2 years after diagnosis and studied its relationship to disease activity in the following years. METHODS: Detailed clinical data on different parameters describing the disease activity in sequential time periods covering the first 2 years after diagnosis were retrieved from the charts of 311 patients with JIA and compared between subtypes. In a cohort of 146 patients, the relation of these different clinical variables to the course of disease in the following 3 years was evaluated. RESULTS: The percentage of time with active disease in the first 2 years differed significantly between subtypes. In all subtypes, a broad spectrum of activity was observed. The time with active disease in the first 2 years was the most significant factor associated with the duration of active disease in the following years. CONCLUSION: Different percentages of time with active disease have been observed between JIA subtypes in the first 2 years. The cumulative duration of activity varied widely within each subtype. Regarding the prognosis of the individual patient, the clinical course in the first 2 years appears to be predictive of the clinical course in the following years. Patients that have less time with active disease in the first 2 years are not likely to develop an unremitting clinical course later on.

[Updated statement by the German Society for Pediatric and Adolescent Rheumatology (GKJR) on the FDA's report regarding malignancies in anti-TNF-treated patients from Aug. 4, 2009]. / Aktualisierte Stellungnahme der GKJR zur Meldung der FDA über Fälle von Malignomen bei Anti-TNF-behandelten Patienten vom 04.08.2009.

TNF inhibitors and other biologicals have greatly expanded the therapeutic options for juvenile idiopathic arthritis (JIA). While the efficacy of etanercept and adalimumab has been proven in randomized controlled clinical trials, their long-term safety remains the subject of ongoing investigations. Reports of leukaemia and tumours in children and adolescents treated with etanercept, infliximab and adalimumab have raised questions about an increased risk for malignancies, with lymphoma accounting for the largest group at 50% of all 48 malignancies reported by the FDA.Consequently, TNF inhibitors should be indicated under careful consideration of individual risk factors, such as increased family occurrence of malignancies, or pre-treatment with carcinogenic substances such as cyclophosphamide. This is particularly true for non-approved substances, and non-approved indications, and for combination therapy of TNF inhibitors with immunosuppressive drugs. On the other hand, however, treatment should not be stopped or started in any patient in whom treatment is necessary due to the current knowledge. Adequate patient information, surveillance and documentation of treatment in the registry of the GKJR is strongly recommended.

Crohn's disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature.

Tumor necrosis factor alpha (TNFalpha) has broad effects on the immune system including lymphoid organ development as well as growth, survival und function of immune cells. TNFalpha has two main functions: regulatory effects and proinflammatory activities. In several diseases such as juvenile and adult "rheumatoid" arthritis, psoriasis and chronic inflammatory bowel disease, the application of TNFalpha-blocking medications has been beneficial. However, induction of inflammation in several organs including the eye, CNS, skin and gastrointestinal tract has been reported. We report on an 11-year-old girl with juvenile idiopathic arthritis, who developed Crohn's disease (CD) while taking etanercept for her arthritis. Etanercept was discontinued and an antibody-based anti-TNF treatment using adalimumab was started, which induced remission of the gastrointestinal symptoms promptly. This case indicates that immunodysregulatory and even proinflammatory effects of etanercept are of relevance in the clinical practice. Furthermore, TNFalpha as a part of its function seems to downregulate mucosal inflammation in CD.

B-cell pathology in juvenile idiopathic arthritis.

Juvenile Idiopathic Arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of different diseases. Due to the promising results of B-cell depleting therapies in rheumatoid arthritis the role of B-cells in autoimmune diseases has to be discussed in a new context. Additionally, experiments in mouse models have shed new light on the antibody-independent role of B-cells in the development of autoimmune diseases. In this review we will discuss the importance of B-cells in the pathogenesis of JIA appraising the question for an immunological basis of B-cell targeted therapy in JIA.

Do B cells play a role in the pathogenesis of juvenile idiopathic arthritis?

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of diseases. The role of B cells (BC) in autoimmune diseases has been put in a new perspective due to the promising results of BC depleting therapies in RA. Experiments in mouse models have shed new light on the Ab-independent role of BC in the pathogenesis of autoimmune diseases. We discuss whether BC play a role in the pathogenesis of JIA appraising the question for an immunological basis of BC directed therapy.

[Hypophosphatasia]. / Hypophosphatasie.

Hypophosphatasia (HP) is an inborn error of bone metabolism transmitted predominantly as an autosomal-recessive trait. It is characterized by a reduced activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSAP) and elevated concentrations of its substrates, including pyrophosphates. Clinical symptoms include defective bone mineralisation with bone deformities, fractures and as recently defined chronic non-bacterial osteomyelitis. Renal damage due to calcification, craniosynostosis and dental abnormalities with premature loss of dentition are further symptoms, which have been described as characteristic in the ESPED inquiry of 2004. Knowledge about the mechanisms underlying cell activation leading to inflammation and tissue destruction is still limited in HP. Recent investigations have provided evidence that calcium pyrophosphate crystals are essentially involved in activating inflammatory signal transduction pathways via different receptors of the innate immune system. Laboratory assays, genetic counselling and testing, and radiologic imaging can confirm the diagnosis. Because symptoms are highly variable in their clinical expression, patients should be followed by a HP-experienced multidisciplinary team (paediatrician, radiologist, orthopedist, neurosurgeon, dentist). At the moment symptomatic support and treatment is most important because a causative therapy, e. g. enzyme replacement therapy, is not yet available.