More severe parotid gland histopathology in paediatric-onset than in adult-onset Sjögren's disease.

OBJECTIVES: The aim of this study was to assess the histopathological features of the parotid glands in patients with paediatric-onset Sjögren's disease (pedSjD) in comparison to patients with adult-onset Sjögren's disease (adSjD). METHODS: This study was performed in Groningen, the Netherlands. Patients with pedSjD from a diagnostic paediatric cohort (n=19), patients with adSjD from a diagnostic adult cohort (n=32) and patients with adSjD who participated in a clinical trial (n=42) with a baseline parotid gland biopsy were included. Parotid gland biopsies were analysed after (immuno)histological staining for SjD-related histopathological markers and compared between groups. RESULTS: All characteristic histopathological features of adSjD were also observed in pedSjD. There were no significant differences in lymphoepithelial lesions or immunoglobulin A (IgA)/IgG plasma cell shift between the pedSjD and the adSjD cohorts. However, compared with the diagnostic adSjD cohort (with comparable total EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores), pedSjD showed more severe lymphocytic infiltration as reflected by a higher focus score (p=0.003), a higher relative surface area of CD45+ infiltrate (p=0.041), higher numbers of B and T lymphocytes/mm2 (p=0.004 and p=0.029, respectively), a higher B/T lymphocyte ratio (p=0.013), higher numbers of CD21+ follicular dendritic cell networks/mm2 (p=0.029) and germinal centres (GC)/mm2 (p=0.002). Compared with the trial adSjD cohort, with significant higher total ESSDAI scores (p=0.001), only the B/T lymphocyte ratio and numbers of GC/mm2 were significantly higher in the pedSjD cohort (p=0.023 and p=0.018, respectively). CONCLUSION: Patients with pedSjD exhibit more pronounced histopathological features compared with patients with adSjD at diagnosis. Notably, the histopathology of patients with pedSjD aligns more closely with that observed in an adSjD clinical trial cohort, with even stronger B lymphocyte involvement.

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children From Wild-type to Population Immunity: A Prospective Multicenter Cohort Study With Real-time Reporting.

BACKGROUND: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. METHODS: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. RESULTS: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. CONCLUSIONS: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections.

[Chronic non-infectious osteomyelitis in children]. / Chronische niet-infectieuze osteomyelitis bij kinderen.

Musculoskeletal pain in common and the differential diagnosis is broad. It is important to recognize the harmful and/or treatable pathology, without performing unnecessary diagnostics. Pattern recognition is crucial. One of the differential diagnostic considerations is chronic non-infectious osteomyelitis (CNO). A relatively unknown auto-inflammatory disease. By presenting three cases, we want to draw attention to this condition and contribute to a better recognition of this disease. We emphasize the importance of doing a total body MRI, when CNO is considered.

Factors associated with care- and health-related quality of life of caregivers of children with juvenile idiopathic arthritis.

OBJECTIVE: This study investigates the relationship of child, caregiver, and caring context measurements with the care-related quality of life (CRQoL) and health-related quality of life (HRQoL) of caregivers of children with juvenile idiopathic arthritis (JIA). METHODS: We performed a cross-sectional analysis of baseline data on caregivers of children with JIA from Canada and the Netherlands collected for the "Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases" study from June 2019 to September 2021. We used the CRQoL questionnaire (CarerQoL), adult EQ-5D-5L, and proxy-reported Youth 5-Level version of EuroQoL (EQ-5D-5L-Y) to assess caregiver CRQoL, caregiver HRQoL, and child HRQoL, respectively. We used a multivariate analysis to assess the relationship between both caregiver CRQoL and HRQoL and patient, caregiver, and caring context measurements. RESULTS: A total of 250 caregivers were included in this study. Most of the caregivers were from the Netherlands (n = 178, 71%) and 77% were females (n = 193). The mean CarerQoL scores was 82.7 (standard deviation (SD) 11.4) and the mean EQ-5D-5L utility score was 0.87 (SD 0.16). Child HRQoL and employment had a positive relationship with both caregiver CarerQoL and EQ-5D-5L utility scores (p < 0.05), while receiving paid or unpaid help had a negative relationship with both scores (p < 0.05). CONCLUSION: Our findings indicated that to understand the impact of JIA on families, we need to consider socio-economic factors, such as employment and support to carry caregiving tasks, in addition to child HRQoL.

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.

Capillary microscopy is a potential screening method for connective tissue disease in children with Raynaud's phenomenon.

BACKGROUND: Nailfold capillary microscopy (NCM) is a cornerstone in the diagnosis of Systemic Sclerosis (SSc) in adulthood. Although Raynaud's phenomenon (RP) is very common in childhood, studies on diagnostic methods to differentiate between primary RP (PRP) and secondary RP (SRP) at a young age are scarce. The aim of this study was to determine the value of NCM in differentiating between PRP and SRP in children and adolescents with RP. METHODS: In this nested case-control study, 83 patients diagnosed with RP and having underwent NCM in childhood were retrospectively included. Based on whether they were diagnosed with a connective tissue disease (CTD) during follow-up, patients were classified as PRP or SRP. NCM was performed by a vascular technician. PRP and SRP patients were compared on demographics, NCM and serology. Variables associated with SRP were included in a multivariate logistic regression model. Predictive values were calculated for NCM, ANA positivity and the combination of NCM and ANA positivity. RESULTS: At the time of the NCM, the mean age of the RP patients was 15.4 ± 2.3 years. Of these patients, 78.3% were classified as PRP and 21.7% as SRP at mean follow-up of 6.4 ± 3.20 years. CTDs were miscellaneous, with only one patient having developed SSc. Of the NCM parameters, only capillary loss was associated with SRP (p = 0.01). In a multivariate logistic regression model including ANA, capillary loss was not a predictor of SRP. In a model without ANAs, capillary loss was an independent predictor (OR = 3.98, CI 95% 1.22-12.99). Capillary loss had a sensitivity of 44.4% and a specificity of 84.4% for SRP. ANA combined with capillary loss had a sensitivity of 66.7% and a specificity of 85.7%. CONCLUSION: Whereas RP in adulthood is most strongly associated with SSc, children with RP seem to be at risk for developing other CTDs with less apparent NCM abnormalities. Of all NCM findings, only capillary loss was predictive for SRP. NCM did not add to the predictive value of ANA screening. However, with a specificity of 84.4% and being non-invasive, NCM shows potential as a screening method for SRP. More research with a larger study population is required before drawing conclusions.

Physical and Psychosocial Health in Pediatric Uveitis Patients.

BACKGROUND: To investigate the possible associations between childhood noninfectious uveitis and cardio-respiratory fitness, physical activity, health related quality of life and fatigue. METHODS: Cross-sectional analysis of 23 patients with noninfectious uveitis, aged 8-18 years. BMI, exercise capacity, muscle strength and physical activity were measured. Health-related quality of life and fatigue were assessed. The results were compared to standardized values for age matched healthy children. RESULTS: Twenty-three patients were included. Children with uveitis had a higher bodyweight and body mass index. Children with uveitis had lower cardio-respiratory fitness and they were less physically active, but they experienced a normal quality of life and normal fatigue. Parents of children with uveitis reported a lower quality of life and more fatigue for their children than parents of healthy children. CONCLUSION: Our study indicates that children with noninfectious uveitis are at risk of developing lower physical and psychosocial health.

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

OBJECTIVE: JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM. METHODS: Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay. RESULTS: Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01). CONCLUSION: Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.

Differences in presentation between paediatric- and adult-onset primary Sjögren's syndrome patients.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a rare disease in paediatric patients. Presenting symptoms differ from those in adult patients. The aim of this study was to evaluate presenting symptoms, classification criteria and clinical assessments, including salivary gland ultrasonography (SGUS), at disease onset in paediatric and adult patients with pSS. METHODS: Data of 23 paediatric- and 33 adult-onset patients with pSS were obtained from our standardised multidisciplinary REpSULT and RESULT cohorts, respectively. Clinical, patient-reported, serological, functional, biopsy and SGUS parameters were compared. RESULTS: In paediatric-onset pSS (pedSS) patients, recurrent parotid gland swelling (91% vs. 49%, p<0.001) and fever (30% vs. 3%, p=0.006) were more often present than in adult-onset patients. In contrast, sicca symptoms of mouth (52% vs. 79%, p=0.046) and eyes (26% vs. 73%, p<0.001) were less common in pedSS patients. In paediatric patients, the entry criteria of the ACR/EULAR classification were most often met due to activity in the glandular domain of the ESSDAI. When applying the ACR/EULAR classification criteria, only 78% of pedSS fulfilled these criteria compared to 100% of adult patients. Abnormal glandular function tests had a greater contribution to fulfilling the criteria in adults, while the biopsy had a greater contribution in paediatric patients. Anti-SSA/Ro serology had similar contribution for both cohorts. SGUS Hocevar score was significantly higher in paediatric compared to adult patients (median 25 vs. 18, p=0.004). CONCLUSION: PedSS has a different presentation than adult-onset pSS. Recurrent parotid gland swelling in paediatric patients should alert clinicians to the potential presence of pSS.

Dutch patients, caregivers and healthcare professionals generate first nationwide research agenda for juvenile idiopathic arthritis.

BACKGROUND: Involving the end-users of scientific research (patients, carers and clinicians) in setting research priorities is important to formulate research questions that truly make a difference and are in tune with the needs of patients. We therefore aimed to generate a national research agenda for Juvenile Idiopathic Arthritis (JIA) together with patients, their caregivers and healthcare professionals through conducting a nationwide survey among these stakeholders. METHODS: The James Lind Alliance method was used, tailored with additional focus groups held to involve younger patients. First, research questions were gathered through an online and hardcopy survey. The received questions that were in scope were summarised and a literature search was performed to verify that questions were unanswered. Questions were ranked in the interim survey, and the final top 10 was chosen during a prioritisation workshop. RESULTS: Two hundred and seventy-eight respondents submitted 604 questions, of which 519 were in scope. Of these 604 questions, 81 were generated in the focus groups with younger children. The questions were summarised into 53 summary questions. An evidence checking process verified that all questions were unanswered. A total of 303 respondents prioritised the questions in the interim survey. Focus groups with children generated a top 5 of their most important questions. Combining this top 5 with the top 10s of patients, carers, and clinicians led to a top 21. Out of these, the top 10 research priorities were chosen during a final workshop. Research into pain and fatigue, personalised treatment strategies and aetiology were ranked high in the Top 10. CONCLUSIONS: Through this study, the top 10 research priorities for JIA of patients, their caregivers and clinicians were identified to inform researchers and research funders of the research topics that matter most to them. The top priority involves the treatment and mechanisms behind persisting pain and fatigue when the disease is in remission.