Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis:does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial

Background: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. Methods: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. Results: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4–10), median 10 months (7–16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6–9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. Conclusions: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. Trial registration: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585.</p

Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis:does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial

Background: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. Methods: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. Results: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4–10), median 10 months (7–16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6–9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. Conclusions: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. Trial registration: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585.</p

Significant pain decrease in children with non-systemic Juvenile Idiopathic Arthritis treated to target:results over 24 months of follow up

Background: The aim of this study was to compare pain-scores in three targeted treatment-strategies in JIA-patients and to identify characteristics predicting persistent pain. Methods: In the BeSt-for-Kids-study 92 DMARD-naïve JIA-patients were randomized in 3 treatment-strategies: 1) initial sequential DMARD-monotherapy 2) initial methotrexate (MTX)/prednisolone-bridging or 3) initial MTX/etanercept. Potential differences in VAS pain scores (0-100 mm) over time between treatment-strategies were compared using linear mixed models with visits clustered within patients. A multivariable model was used to assess the ability of baseline characteristics to predict the chance of high pain-scores during follow-up. Results: Pain-scores over time reduced from mean 55.3 (SD 21.7) to 19.5 (SD 25.3) mm after 24 months. On average, pain-scores decreased significantly with β -1.37 mm (95% CI -1.726; -1.022) per month. No significant difference was found between treatment-strategies (interaction term treatment arm*time (months) β (95% CI) arm 1: 0.13 (-0.36; 0.62) and arm 2: 0.37 (-0.12; 0.86) compared to arm 3). Correction for sex and symptom duration yielded similar results. Several baseline characteristics were predictive for pain over time. Higher VAS pain [β 0.44 (95% CI 0.25; 0.65)] and higher active joint count [0.77 (0.19; 1.34)] were predictive of higher pain over time, whereas, low VAS physician [-0.34 (-0.55; -0.06)], CHQ Physical [-0.42 (-0.72; -0.11)] and Psychosocial summary Score [-0.42 (-0.77; -0.06)] were predictive of lower pain. Conclusions: Treatment-to-target seems effective in pain-reduction in non-systemic JIA-patients irrespective of initial treatment-strategy. Several baseline-predictors for pain over time were found, which could help to identify patients with a high risk for development of chronic pain. Trial registration: Dutch Trial Registry number 1574.</p

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 (Χ(2), 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

DIFFUSE JUVENILE SYSTEMIC SCLEROSIS PATIENTS SHOW DISTINCT ORGAN INVOLVEMENT, ANTIBODY PATTERN AND HAVE SIGNIFICANTLY MORE SEVERE DISEASE IN THE LARGEST JSSC COHORT OF THE WORLD. RESULTS FROM THE JUVENILE SCLERODERMA INCEPTION COHORT

Peer reviewe

American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus

10.1002/acr.23834ARTHRITIS CARE & RESEARCH715579-59

Correlations between capillary density and degree of skin pigmentation in healthy children analysed by nailfold video capillaroscopy

Background: Nailfold video capillaroscopy (NVC) is a simple, non-invasive diagnostic tool but studies with normal values for capillary density in healthy children are rare. Ethnic background seems to play a role in capillary density; however, this is not well substantiated yet. In this work, we set out to evaluate influence of ethnic background/skin pigmentation and age on capillary density reading in healthy children. Secondary aim was to investigate whether there is a significant difference in density between different fingers within the same patient. Methods: Between 2016 and 2021, healthy children from schools around AUMC were approached, by convenience sampling. In this cross-sectional study, capillaroscopic images were obtained in a one-time videocapillaroscopy (×200 magnification) addressing the capillary density (i.e., number of capillaries per linear millimetre in the distal row). This parameter was compared to age, sex, ethnicity, skin pigment grade (I-III) and between eight different fingers, excluding the thumbs. Density differences were compared by ANOVAs. Correlations between capillary density and age were calculated with Pearson correlations. Results: We investigated 145 healthy children with mean age of 11.03 years (SD 3.51). The range of capillary density was 4–11 capillaries per millimetre. We observed a lower capillary density in the ‘grade II’ (6.4±0.5 cap/mm, P&lt;0.001) and ‘grade III’ (5.9±0.8 cap/mm, P&lt;0.001) pigmented-classified groups compared to the ‘grade I’ group (7.0±0.7 cap/mm). We did not find a significant correlation between age and density in the overall group. The fifth fingers on both sides had a significantly lower density compared to the other fingers. Conclusions: Healthy children &lt;18 years with higher degree of skin pigmentation show a significantly lower nailfold capillary density. In subjects with an African/Afro-Caribbean and North-African/Middle- Eastern ethnicity, a significantly lower mean capillary density was observed compared to subjects with the Caucasian ethnicity (P&lt;0.001, and P&lt;0.05, respectively. There were no significant differences between other ethnicities. No correlation was found between age and capillary density. The fifth fingers on both hands displayed lower capillary density compared to the other fingers. This needs to be taken into account when describing lower density in paediatric patients with connective tissue diseases. Keywords: Nailfold videocapillaroscopy (NVC); healthy children; capillary density; ethnic background; skin pigmentatio

Rituximab in Idiopathic Pulmonary Hemosiderosis in Children: A Novel and Less Toxic Treatment Option

Idiopathic pulmonary hemosiderosis (IPH) is a rare, potentially life-threatening chronic disease. Steroids are the cornerstone of treatment, even though toxicity and side-effects are very common. Recently, rituximab (RTX) has been suggested as a treatment option, although evidence for its efficacy and long-term safety is lacking. We describe the disease course of two pediatric patients with IPH that were treated with RTX for over 4 years. Demographics, treatments, and clinical variables such as growth, infections, imaging follow-up by CT, and data from pulmonary function tests were retrospectively described. These are the first two cases described with a long-term follow-up of pediatric IPH patients treated with RTX. RTX was well-tolerated and prevented outbreaks of bleeding. In addition, RTX had a robust steroid-sparing effect resulting in the improvement of growth, pulmonary function, and CT abnormalities

Congenital syphilis, the great imitator—case report and review

Syphilis is caused by a spirochaete bacterium called Treponema pallidum. Vertical transmission of spirochaetes can lead to congenital infection of the fetus in pregnant women who are inadequately treated or not treated at all, causing various clinical manifestations including stillbirth and neonatal death, cutaneous and visceral manifestations, or asymptomatic infection. We present a severe case of syphilis in a 3-month-old boy with skin lesions, portal hypertension, and anaemia. Because the mother was tested negative for syphilis antibodies at 16 weeks of gestation, a diagnosis of congenital syphilis was initially not considered. This case shows that transmission of T pallidum can still occur in high-income countries with a high rate of antenatal screening. Early recognition might be hampered if physicians do not consider congenital syphilis as a possible diagnosis. Congenital syphilis should be considered in any severe and diagnostically challenging infectious disease case, even in the context of negative antenatal screening