Prospective multicenter evaluation of adherence to the Dutch guideline for children aged 0-16 years with fever without a source-febrile illness in children (FINCH) study.

Evaluation of guidelines in actual practice is a crucial step in guideline improvement. A retrospective evaluation of the Dutch guideline for children with fever without an apparent source (FWS) showed 50% adherence in young infants. We prospectively evaluated adherence to the Dutch guideline and its impact on management in current practice. Prospective observational multicenter cross-sectional study, including children 3 days to 16 years old presented for FWS at one of seven emergency departments in participating secondary and tertiary care hospitals in the Netherlands. Adherence to the Dutch FWS guideline, adapted from the National Institute for Health and Care Excellence (NICE) guideline, was evaluated, and patterns in non-adherence and the impact of non-adherence on clinical outcomes and resource use were explored. Adherence to the guideline was 192/370 (52%). Adherence was lowest in patients categorized as high risk for severe infection (72/187, 39%), compared to the low-risk group (64/73, 88%). Differences in adherence were significant between risk categories (P < 0.001) but not between age categories. In case of non-adherence, less urinalysis, fewer bacterial cultures (blood, urine, and cerebral spinal fluid), and less empirical antibiotic treatment were performed (P < 0.050). Clinical outcomes were not significantly different between the non-adherence and the adherence group, particularly regarding missed severe infections. CONCLUSIONS: We found a high non-adherence rate of 48%, which did not lead to unfavorable clinical outcomes. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures, viral testing, and antibiotic treatment. WHAT IS KNOWN: • Despite the development of national guidelines, variation in practice is still substantial in the assessment of febrile children to distinguish severe infection from mild self-limiting disease. • Previous retrospective research suggests low adherence to national guidelines for febrile children in practice. WHAT IS NEW: • In case of non-adherence to the Dutch national guideline, similar to the National Institute for Health and Care Excellence (NICE) guideline from the United Kingdom, physicians have used fewer resources than the guideline recommended without increasing missed severe infections.

Population Pharmacokinetics of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

BACKGROUND AND OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. MATERIALS AND METHODS: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. RESULTS: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. CONCLUSIONS: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

Pharmacodynamics of rituximab in paediatric immune mediated diseases: B cell depletion and repopulation, effects on immunoglobulin levels and risk for infections.

OBJECTIVES: Rituximab (RTX), used for treatment in paediatric immune-mediated diseases, can lead to hypogammaglobulinaemia and thus to an increased risk of infection, but data on these adverse effects in children are scarce. We aimed to describe the pharmacodynamics of RTX by time to B cell repopulation in paediatric immune-mediated diseases and to assess whether low post-RTX immunoglobulin levels were associated with frequency and severity of infections. METHODS: Data of children with autoimmune diseases (AID), immune dysregulation (ID), haematological diseases (HD) and renal diseases (RD), including immunoglobulin levels pre-/post-RTX and occurrence of infections, who had received RTX at our centre were retrospectively collected. B cell depletion was defined as B cells <10 cells/µl. RESULTS: Post-RTX B cell depletion was achieved in 45/49 patients. In 30/45 patients with B cell repopulation, median time to repopulation was 166 days (IQR 140-224): AID group (n=9) (183 days (IQR 156-239), ID group (n=6) 170 days (IQR 128-184), HD group (n=7) 139 days (IQR 127-294), RD group (n=7) 160 days (IQR 121-367). Severe infections leading to hospitalisation occurred in 7/52 (13.5%) patients: ID (n=3), HD (n=1), RD (n=3). After RTX treatment, 13/52 patients (25%) had low IgG levels for their age at least once, 11/13 had an infection during low IgG but only 2/13 had a severe infection. Low IgG was not associated with severe infection (p=0.459). CONCLUSIONS: Time to B cell repopulation post-RTX ranged individually but did not significantly differ between paediatric patient groups. Severe infections were non-frequent and not associated with low (post-RTX) IgG levels.

Double inversion recovery MRI versus contrast-enhanced MRI for evaluation of knee synovitis in juvenile idiopathic arthritis.

BACKGROUND: Double inversion recovery (DIR) MRI has the potential to accentuate the synovium without using contrast agents, as it allows simultaneous signal suppression of fluid and fat. The purpose of this study was (1) to compare DIR MRI to conventional contrast-enhanced (CE) MRI for delineation of the synovium in the knee in children with juvenile idiopathic arthritis (JIA) and (2) to assess the agreement between DIR MRI and CE-MRI regarding maximal synovial thickness measurements. RESULTS: In this prospective study, 26 children with JIA who consecutively underwent 3.0-T knee MRI between January 2018 and January 2021 were included (presence of knee arthritis: 13 [50%]; median age: 14 years [interquartile range [IQR]: 11-17]; 14 girls). Median confidence to depict the synovium (0-100 mm visual analogue scale; scored by 2 readers [consensus based]) was 88 (IQR: 79-97) for DIR MRI versus 100 (IQR: 100-100) for CE-MRI (p value = < .001). Maximal synovial thickness per child (millimeters; scored by 4 individual readers) on DIR MRI was greater (p value = < .001) in the children with knee arthritis (2.4 mm [IQR: 2.1-3.1]) than in those without knee arthritis (1.4 mm [IQR: 1.0-1.6]). Good inter-technique agreement for maximal synovial thickness per child was observed (rs = 0.93 [p value = < .001]; inter-reader reliability: ICC DIR MRI = 0.87 [p value = < .001], ICC CE-MRI = 0.90 [p value = < .001]). CONCLUSION: DIR MRI adequately delineated the synovium in the knee of children with JIA and enabled synovial thickness measurement similar to that of CE-MRI. Our results demonstrate that DIR MRI should be considered as a child-friendly alternative to CE-MRI for evaluation of synovitis in children with (suspected) JIA.

Nailfold capillary scleroderma pattern may be associated with disease damage in childhood-onset systemic lupus erythematosus: important lessons from longitudinal follow-up.

OBJECTIVES: To observe if capillary patterns in childhood-onset SLE (cSLE) change over time and find associations between a capillary scleroderma pattern with disease activity, damage or scleroderma-like features. METHODS: Clinical and (yearly) capillaroscopy data from a longitudinal cohort of patients with cSLE (minimum of four Systemic Lupus International Collaborating Clinics (SLICC) criteria, onset <18 years) were analysed. Disease activity was measured by Systemic Lupus Erythematosus Activity Index (SLEDAI) and disease damage by SLICC Damage Index. A scleroderma pattern was defined according to the 'fast track algorithm' from the European League Against Rheumatism Study Group on Microcirculation in Rheumatic Diseases. An abnormal capillary pattern, not matching a scleroderma pattern, was defined as 'microangiopathy'. RESULTS: Our cohort consisted of 53 patients with cSLE with a median disease onset of 14 years (IQR 12.5-15.5 years), median SLEDAI score at diagnosis was 11 (IQR 8-16), median SLEDAI at follow-up was 2 (IQR 1-6). A scleroderma pattern (ever) was seen in 18.9%, while only 13.2% of patients had a normal capillary pattern. Thirty-three patients had follow-up capillaroscopy of which 21.2% showed changes in type of capillary pattern over time. Type of capillary pattern was not associated with disease activity. Raynaud's phenomenon (ever) was equally distributed among patients with different capillaroscopy patterns (p=0.26). Anti-ribonucleoprotein antibodies (ever) were significantly more detected (Χ2, p=0.016) in the scleroderma pattern subgroup (n=7 of 10, 70%). Already 5 years after disease onset, more than 50% of patients with a scleroderma pattern had SLE-related disease damage (HR 4.5, 95% CI 1.1 to 18.8, p=0.034), but they did not develop clinical features of systemic sclerosis at follow-up. Number of detected fingers with a scleroderma pattern was similar between cSLE, juvenile systemic sclerosis and juvenile undifferentiated connective tissue disease. CONCLUSION: This longitudinal study shows that the majority of capillary patterns in cSLE are abnormal and they can change over time. Irrespective of disease activity, a capillary scleroderma pattern in cSLE may be associated with higher risk of SLE-related disease damage.

Rarities in rare: illuminating the microvascular and dermal status in juvenile localised scleroderma. A case series.

OBJECTIVES: To assess the (structural and functional) characteristics of the microvascular and dermal status in juvenile localised scleroderma (jLoS), using novel non-invasive standardised research tools commonly used in adult systemic sclerosis (SSc). METHODS: Ten consecutive patients with a confirmed jLoS diagnosis were studied cross-sectionally in this two-centre case series. For each patient, the most prominent lesion (i.e., "target lesion") was chosen for further examination of the centre, edge and contralateral unaffected site. High-frequency ultrasonography was used to determine dermal thickness, durometer for skin hardness, and laser speckle contrast analysis (LASCA) for a dynamical evaluation of the microcirculation. The structure of the microcirculation was evaluated at the nailfolds of the 2nd-5th finger bilaterally, using nailfold videocapillaroscopy (NVC). RESULTS: 6 linear and 4 plaque subtype jLoS lesions were included. Dermal thickness was thinner at the centre of the "target lesions" vs. the edges (p<0.001) and control sites (p<0.001). Skin hardness was harder at the centre of the "target lesions" vs. the edges (p=0.012) and control sites (p=0.003). A higher perfusion was found in the centre of the "target lesion" (124.87±66.40 PU) vs. the edges (87.27±46.40 PU; p<0.001) and control sites (67.85±37.49; p<0.001). Of note, all patients had a "non-scleroderma" pattern on NVC. CONCLUSIONS: This case series suggests the supportive value of both microcirculatory and dermal assessments of skin lesions using novel non-invasive research tools, adopted from adult SSc, for (j)LoS.

Population Pharmacokinetics of Infliximab in Children with Juvenile Idiopathic Arthritis.

BACKGROUND: The recommended infliximab (IFX) dose in (pediatric) rheumatology practice is 3-6 mg/kg every 4-8 weeks. Higher dosage regimens (>10 mg/kg) of IFX are effective and safe. To optimize IFX treatment in patients with juvenile idiopathic arthritis (JIA), therapeutic drug monitoring might be beneficial. To support routine therapeutic drug monitoring of IFX and regimen optimization for patients with JIA, in-depth knowledge of the pharmacokinetic (PK) variability of IFX is needed. As soon as the optimal therapeutic drug ranges are known, PK model-based simulation can be used to individualize drug dosing recommendations. In this study, a population PK model for IFX is described for patients with JIA. METHODS: Data including IFX trough concentrations and anti-IFX antibodies of 27 pediatric patients with JIA on IFX maintenance treatment were retrieved from electronic charts. Three population PK models from the literature were validated for the authors' data set using the nonlinear mixed-effects modeling program NONMEM. A novel population PK model was developed based on the study data. RESULTS: A total of 65 blood samples obtained after a median of 32 days after the last IFX infusion (interquartile range 28-42) were analyzed. The 3 published models underpredicted the observed trough concentrations. A newly developed one-compartment model best described the data corresponding to IFX serum concentration over time in patients with JIA. CONCLUSIONS: This study shows a novel PK model for IFX in patients with JIA. The data show that different PK models are needed for different age categories (children or adults) and different diseases.

Anti-rituximab antibodies affect pharmacokinetics and pharmacodynamics of rituximab in children with immune-mediated diseases.

OBJECTIVES: Rituximab (RTX) is a chimeric monoclonal CD20-antibody. Lack of efficacy has been suggested to be related to the presence of anti-drug antibodies (ADA). The aims of this study were to determine if ADA impact the pharmacokinetics (PK) and pharmacodynamics (PD) of RTX in children, whether the formation of ADA differs between various immune-mediated diseases and if it is related to the occurrence of infusion-related reactions (IRR). METHODS: All children <18 years who had received RTX treatment in our centre between December 2006 and February 2020 with known ADA/RTX-levels, were retrospectively included. The presence of ADA was defined as a titre >8 AU/ml. RESULTS: Of twenty-six children treated with RTX for various immune-mediated diseases, six patients were ADA-positive (23.1%). In all ADA-positive patients, RTX concentrations were undetectable in contrast to ADA-negative patients (median RTX concentration 3.1 µg/ml; IQR 0.57-12.0; p<0.001). Failure of B cell depletion was found in 5/6 ADA-positive and 1/19 ADA-negative patients (p=0.003). In SLE-patients, 50.0% (n=4/8) had developed RTX-ADA. Severe anaphylaxis (n=3) occurred only in the ADA-positive group. CONCLUSIONS: In our cohort of paediatric patients, undetectable RTX concentrations were found in ADA-positive patients, indicative that these ADA have a PK impact. RTX-ADA also seem to affect the PD, as in the majority of these patients, B cell depletion failed. ADA were most present in SLE-patients and anaphylactic reactions occurred only in ADA-positive patients. With this knowledge, a change of drug might be considered in the presence of RTX-ADA.

Reliable detection of subtypes of nailfold capillary haemorrhages in childhood-onset systemic lupus erythematosus.

OBJECTIVES: In systemic lupus erythematosus (SLE), it is necessary to obtain biomarkers that predict cardiovascular complications due to premature atherosclerosis, which is related to endothelial dysfunction. Nailfold capillary abnormalities might be a biomarker for endothelial dysfunction. In adults and children with SLE, nailfold capillary haemorrhages have shown to be significantly correlated with disease activity. Recently, different subtypes of capillary haemorrhages have been described in childhood-onset SLE (cSLE). The aim of the current study was to assess the inter- and intra-rater reliability of observations of different subtypes of haemorrhages in cSLE patients. METHODS: Five raters blindly evaluated 140 capillaroscopy images from 35 cSLE-patients (diagnosed according to the 2012 SLICC criteria). The images were assessed qualitatively (present or absent) and quantitatively (total number) on four different subtypes of haemorrhages: 1) punctate extravasations, 2) perivascular haemorrhage, 3) large confluent haemorrhage and 4) non-definable. As subgroups 1) and 2) were interpreted as a continuous spectrum, a post-hoc analysis with "merged" (mean) kappa/ICC was additionally calculated as one sub-group. RESULTS: Qualitative assessment showed a kappa 0.65 (95% CI: 0.60-0.70) for "punctate extravasations and perivascular haemorrhages merged" and a kappa 0.78 (95% CI: 0.72-0.83) for large confluent haemorrhages. For the quantitative assessment, ICC was 0.82 (95% CI: 0.76-0.87) for the "merged groups" and ICC 0.93 (95% CI: 0.91-0.95) for large confluent haemorrhages. CONCLUSIONS: Our study shows that different subtypes of capillary haemorrhages in cSLE-patients could be reliably reproduced by different raters. This confirms our recent observation of perivascular extravasations as a subgroup of capillary haemorrhage in cSLE that might reflect endothelial dysregulation.

Nailfold capillary abnormalities in childhood-onset systemic lupus erythematosus: a cross-sectional study compared with healthy controls.

OBJECTIVES: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients. METHODS: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases. RESULTS: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001). CONCLUSIONS: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.

Exploring contrast-enhanced MRI findings of the clinically non-inflamed symptomatic pediatric wrist.

BACKGROUND: Knowledge of the synovial and tenosynovial appearance of the clinically non-arthritic symptomatic juvenile wrist using contrast-enhanced magnetic resonance imaging (MRI) is sparse. OBJECTIVES: To analyze contrast-enhanced MRI findings of the clinically non-inflamed symptomatic pediatric wrist, focusing on the enhancing synovial and tenosynovial membrane. To evaluate the coexistent presence of (teno)synovial enhancement, joint fluid, bony depressions and medullary changes suggestive of bone marrow edema. MATERIALS AND METHODS: We included 20 children (15 girls; age range: 7.5-17.6 years) who underwent contrast-enhanced MRI of the wrist, based on initial clinical indication, and eventually turned out to be unaffected by arthritic or orthopedic disorders. Various imaging characteristics of the synovium, tenosynovium, joint fluid, bone tissue and bone marrow were evaluated using existing MRI scoring systems. RESULTS: In 3/20 (15%) children, mild or moderate-severe synovial enhancement was observed and 2/20 (10%) children showed mild tenosynovial enhancement/thickening. Joint fluid (11/20 children; 55%), bony depressions (20/20 children; 100%) and medullary changes suggestive of bone marrow edema (6/20; 30%) were found in a substantial percentage of children. The most frequently observed combination of coexisting imaging characteristics was bony depressions with ≥2 mm joint fluid, which was found in 7/20 (35%) children. Simultaneous presence of synovial and tenosynovial enhancement/thickening, bony depressions and medullary changes suggestive of bone marrow edema was observed in one child. CONCLUSION: Several juvenile idiopathic arthritis-relevant MRI characteristics can be observed in the clinically non-inflamed symptomatic pediatric wrist.

Experiences, perspectives and expectations of adolescents with juvenile idiopathic arthritis regarding future work participation; a qualitative study.

BACKGROUND: Having Juvenile idiopathic Arthritis (JIA) has widespread implications for a person's life. Patients have to deal with recurring arthritis, characterized by pain often accompanied by a loss of energy. Since JIA often persists into adulthood, patients with JIA are likely to encounter difficulties in their working life. We expect that the experiences in school life may be comparable to the barriers and opportunities which patients affected by JIA encounter in adult working life. Therefore, the aim of this study was to elicit the experiences during school life and the perspectives and expectations regarding future work participation of adolescents with JIA. METHODS: This study used individual, semi-structured interviews and followed a predefined interview guide. Participants between 14 and 18 years of age (n = 22) were purposively selected to achieve a broad range of participant characteristics. Open coding was performed, followed by axial coding and selective coding. RESULTS: Great differences were seen in the support and understanding that adolescents received in dealing with JIA at school, leisure activities and work. Varying approaches were mentioned on how to pursue a desired vocation. Perspectives regarding disclosure varied. Participants wished to be approached like any other healthy adolescent. Expectations regarding work participation were positively expressed. CONCLUSION: This study showed that participants often disregarded having JIA when making plans for their future career. Facilitating an open discussion about the possible limitations accompanying JIA with educators and employers might prevent overburden and increase the chance of starting a career which would accommodate the patient with JIA in the near and distant future.

MRP8/14 and neutrophil elastase for predicting treatment response and occurrence of flare in patients with juvenile idiopathic arthritis.

OBJECTIVE: To study two neutrophil activation markers, myeloid-related protein (MRP) 8/14 and neutrophil elastase (NE), for their ability to predict treatment response and flare in patients with JIA. METHODS: Using samples from two cohorts (I and II), we determined MRP8/14 and NE levels of 32 (I) and 81 (II) patients with new-onset, DMARD-naïve arthritis and compared patients who responded to treatment (defined as fulfilling ≥ adjusted ACRpedi50 response and/or inactive disease) with non-responders (defined as fulfilling < adjusted ACRpedi50 response and/or active disease) at 6 and 12 months. Secondly, we compared biomarker levels of 54 (I) and 34 (II) patients with clinically inactive disease who did or did not suffer from a flare of arthritis after 6 or 12 months. Receiver operating characteristic analyses were carried out to study the predictive value of MRP8/14 and NE for treatment response and flare. RESULTS: For both cohorts, baseline MRP8/14 and NE levels for patients who did or did not respond to treatment were not different. Also, MRP8/14 and NE levels were not different in patients who did or did not flare. Receiver operating characteristic analysis of MRP8/14 and NE demonstrated areas under the curve <0.7 in both cohorts. CONCLUSION: In our cohorts, MRP8/14 and NE could not predict treatment response. Also, when patients had inactive disease, neither marker could predict flares.

Capillaroscopy in childhood-onset systemic lupus erythematosus: a first systematic review.

OBJECTIVES: Recently, a systematic review indicated that, compared to healthy controls, adult patients with systemic lupus erythematosus (SLE) show a significantly more abnormal capillary morphology and greater number of haemorrhages in nailfold capillaroscopy and that these capillary changes are associated with disease activity. As yet, no systematic literature evaluation of capillaroscopy in childhood-onset SLE (cSLE) has been performed. Therefore, we aimed to systematically review the literature on nailfold capillary characteristics in cSLE. METHODS: Search terms "SLE or Lupus", "Capillaroscopy" and "Juvenile or Childhood or Paediatric or Child" were used in PubMed, Embase and Web of Science. Capillary findings were evaluated according to the current international consensus-based definitions for analysis of capillaroscopic characteristics from the European League against Rheumatism (EULAR) Study Group on Microcirculation in Rheumatic Diseases (SG MC/RD). RESULTS: After screening eighty search hits, six articles were retained, two of which were case-control studies and four case series. For capillary density, no difference was found between cSLE and healthy controls (one study). Differences in capillary diameter, capillary morphology, haemorrhages and semi-quantitative score were inconclusive or non-interpretable. A scleroderma pattern was not detected in the case control studies but was reported in a minority of cSLE patients in 3 out of 4 case series. CONCLUSIONS: Literature on nailfold capillary findings in cSLE is scarce and inconclusive. To evaluate capillary characteristics in cSLE, prospective longitudinal studies are needed. Future studies should use uniform definitions for capillary characteristics and findings should be compared with healthy controls, matched for age and ethnicity. The EULAR SG MC/RD is stepping up to this need.

Consider the wrist: a retrospective study on pediatric connective tissue disease with MRI.

The aim of this study is to describe the clinical characteristics and MRI findings of the wrist in a cohort of children suffering from connective tissue disease with musculoskeletal involvement. Ten patients with pediatric connective tissue disease [median age 14.7 years (IQR 12.7-16.6 years), 70% female] were identified from a large MRI database. Clinical findings during the disease course were retrospectively obtained from patient charts and findings at the time of MRI were prospectively registered in the MRI database. MRI wrist datasets were evaluated by three readers in consensus for synovitis, tenosynovitis, bone marrow changes, bone erosions and myositis. Patients suffered from connective tissue disease with clinical overlap of subtypes systemic lupus erythematosus, Sjögren syndrome and dermatomyositis. Median onset of disease was at 12.3 years (IQR 7.8-14.8 years). Clinical arthritis activity was scored low (median visual analogue scale physician 19, IQR 7-31). Notwithstanding, extensive inflammatory abnormalities such as synovitis and tenosynovitis were found in the wrist of 7/10 patients. Osteochondral involvement was detected in 3/10 patients. In a small cohort of children with connective tissue disease and musculoskeletal symptoms, severe inflammatory abnormalities of the involved wrist were present in the MRI, while clinical disease scores suggested mild disease activity. Therefore, clinicians should consider the wrist as vulnerable for joint damage and can add MRI as a helpful tool in the management of patients with pediatric connective tissue disease and musculoskeletal involvement.

Prolonged time between intravenous contrast administration and image acquisition results in increased synovial thickness at magnetic resonance imaging in patients with juvenile idiopathic arthritis.

BACKGROUND: Post-contrast synovial thickness measurement is necessary for scoring disease activity in juvenile idiopathic arthritis (JIA). However, the timing of post-contrast sequences varies widely among institutions. This variation in timing could influence thickness measurements. OBJECTIVE: To measure thickness of the synovial membrane on early and late post-contrast knee magnetic resonance (MR) images of patients with JIA. MATERIALS AND METHODS: Dynamic contrast-enhanced T1-weighted knee MR images of 53 children with JIA with current or past knee arthritis were used to study synovial thickness at time point 1 (about 1 min) and time point 2 (about 5 min after contrast administration). Two experienced readers, who were blinded for the time point, independently measured synovial thickness at a predefined, marked location in the patellofemoral compartment on randomized images. Synovial thickness at the two time points was compared using the Wilcoxon signed rank test. Repeatibility of the synovial thickness measurements was studied using intraclass correlation coefficients and Bland-Altman plots. RESULTS: Median synovial thickness of the 53 patients (median age: 13.5 years, 59% female) increased with prolonged post-contrast interval with a synovial thickness of 1.4 mm at time point 1 and a synovial thickness of 1.5 mm at time point 2 (P<0.001). Repeated synovial thickness measurements showed an intraclass correlation coefficient (ICC) of 0.75, P<0.05 for time point 1 and an ICC of 0.91, P<0.05 for time point 2. CONCLUSION: Post-contrast synovial membrane thickness measurements are time-dependent. Therefore, standardization of post-contrast image acquisition timing is important to achieve consistent grading of synovial inflammation.

Lyme Borreliosis in Children: A Tertiary Referral Hospital-Based Retrospective Analysis.

Lyme borreliosis (LB) is an endemic disease in adults in Western countries. Although children may also be infected, pediatric studies on LB are scarce. This study aims to estimate the incidence of LB among children with a clinical suspicion for Lyme in a tertiary referral center in the Netherlands. Patient chart data on medical history, clinical signs and symptoms, diagnostic test results and diagnoses were collected using standardized case record forms. Patients were categorized based on clinical and laboratory findings using a modified, previously published classification system. We included 325 children, with a median age of 11.9 years, of whom 61.8% were female. LB was diagnosed in 38 of the referred children (11.7%). However, of the 85 patients who were specifically referred to the Lyme clinic, 28 (32.9%) were diagnosed with LB. Of the specifically referred Lyme-positive patients, 11 (39.3%) had a definitive LB diagnosis. Twelve children had a posttreatment LB syndrome. In line with previous reports in adults, only a small proportion of children referred with a suspicion of LB were diagnosed with definite or probable LB, which illustrates the difficulty in diagnosing LB by the general practitioner or pediatrician in a district hospital.

Definitions and Outcome Measures in Pediatric Functional Upper Gastrointestinal Tract Disorders: A Systematic Review.

OBJECTIVES: Functional disorders of the upper gastrointestinal tract are frequently diagnosed in children. Four different clinical entities are addressed by the Rome III committee: functional dyspepsia (FD), cyclic vomiting syndrome (CVS), adolescent rumination syndrome (ARS), and aerophagia. Management of these disorders is often difficult leading to a wide variety in therapeutic interventions. We hypothesize that definitions and outcome measures in these studies are heterogeneous as well. Our aim is to systematically assess how these disorders and outcomes are defined in therapeutic randomized controlled trials (RCTs). STUDY DESIGN: CENTRAL, Embase, and MEDLINE/PubMed were searched from inception to February 25, 2015. Search terms were FD, CVS, ARS, and aerophagia. Therapeutic RCTs, or systematic reviews of RCTs, in English language including subjects ages 4 to 18 years (0-18 years for CVS) were evaluated. Quality was assessed using the Delphi list. RESULTS: A total of 1398 articles were found of which 8 articles were included. Seven concerned FD and 1 concerned CVS. In all of the studies, Rome criteria or similar definitions were used; all the studies however used different outcome measures. Seventy-five percent of the trials were of good methodological quality. Only 57% used validated pain scales. CONCLUSIONS: Different outcome measures are used in therapeutic trials on functional disorders of the upper gastrointestinal tract. There is a clear paucity of trials evaluating different treatment regimens regarding CVS, ARS, and aerophagia. Uniform definitions, outcome measures, and validated instruments are needed to make a comparison between intervention studies possible.