To analyse the internal consistency of an adaption of the methotrexate intolerance severity score (MISS); and to describe and compare the level of methotrexate intolerance evaluated by the MISS in ...Danish children with juvenile idiopathic arthritis (JIA) or acute lymphoblastic leukaemia (ALL), treated with low-dose methotrexate (MTX).
Cross-sectional study of children diagnosed with JIA or ALL, treated with low-dose MTX, aged 9 years or above, and cognitively intact. The patient's parents completed the MISS. MTX intolerance was defined as a total MISS score above 6.
We enrolled 120 children with JIA and 23 children with ALL. The MISS had a good internal consistency in the JIA group. The median MISS score was higher in the JIA group than in the ALL group (JIA: 8; ALL: 1; p<0.0001); and the JIA group had a larger proportion of MTX intolerant children than the ALL group (JIA: 73/120; ALL: 4/23; p<0.001). Within both the JIA group and the ALL group, the MISS total score was not significantly correlated with age, MTX dose or the duration of low-dose MTX treatment.
In the JIA group the level of MTX intolerance was higher and more attributed to anticipatory, associative and behavioural symptoms than in the ALL group. The MISS may help to uncover whether MTX intolerance is present and which aspects are affected in the individual patient, thus guiding intervention. The MISS may also be applicable within leukaemia care.
Context: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the ...level of MTX-induced nausea, possibly due to genetic factors.
To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.
Methods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children's completion of a nausea diary (min. 7 days) and the parents' completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744).
Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3-15.1). The median MTX dose was 9.7 mg/m
/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations.
Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).
Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.
Prevention of illness due to infection by influenza viruses is important for children with rheumatic diseases. Biological disease modifying antirheumatic drugs have become increasingly important in ...the treatment of juvenile idiopathic arthritis, and combinations of immunosuppressive drugs are used for the treatment of systemic disorders, which increase the risk of secondary immunodeficiency. Therefore, we investigated whether children with rheumatic disease can mount a protective antibody response after influenza immunization.
The prospective multicentre cohort study was conducted in Denmark during the influenza season 2015-2016. Children with rheumatic disease aged six months to 19 years were eligible. Controls were immunologically healthy children. A blood sample was collected before and after vaccination and analysed by haemagglutination inhibition (HI) assay for the 2015-2016 influenza vaccine-strains. In case of flu-like symptoms the child was tested for influenza. For statistical analyses the patients were grouped according to medical treatment or disease.
A total of 226 patients and 15 controls were enrolled. No differences were found for the increase of antibodies from pre-vaccine to post-vaccine between the groups in our primary analyses: A/Cal H1N1pdm09 (p = 0.28), A/Swi H3N2 (p = 0.15) and B/Phu Yamagata (p = 0.08). Only when combining patients across groups a lower increase in antibodies was found compared to controls. Among all patients the pre-vaccine rates for seroprotection using the HI-titer cut-off ≥ 40 were 93.1-97.0 % for all three strains. For seroprotection using the HI-titer cut-off ≥ 110 the pre-vaccine rates for all patients were 14.9-43.6 % for all three strains and an increase in the proportions of patients being seroprotected after vaccination was found for A/Cal H1N1pdm09 and A/Swi H3N2. None of the children with flu-like symptoms tested positive for the vaccine strains.
Children with rheumatic diseases increase in antibody titres after influenza immunization, however, it remains uncertain whether a protective level is achieved.
The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile ...idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Danish language. The reading comprehension of the questionnaire was tested in ten JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, test–retest reliability and construct validity (convergent and discriminant validity). A total of 303 JIA patients (7.9% systemic, 35% oligoarticular, 22.1% RF negative polyarthritis, 35% other categories) and 99 healthy children, were enrolled in three centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Danish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.
Methotrexate (MTX) plays a key role when treating juvenile idiopathic arthritis (JIA), but MTX-intolerance is challenging. MTX-treatment might affect the liver, causing elevated levels of alanine ...aminotransferase (ALT), yet the role of ALT-levels in MTX-intolerance in JIA remains unclear. Our study aimed to investigate the association between ALT-levels during MTX-treatment and MTX-intolerance in JIA. Children (> 9 years old) diagnosed with JIA and treated with MTX (> 6 weeks) were eligible for enrollment. MTX-intolerance was assessed using the Methotrexate Intolerance Severity Score (MISS), completed by the parents, and defined as MISS ≥ 6 with at least 1 point for a behavioral/anticipatory/associative symptom. ALT-levels were determined at enrollment. A total of 118 children were enrolled (80 girls; 38 boys). MTX-intolerance was registered in 61%. ALT-levels did not differ between the MTX-intolerant group (median = 17.0 U/L IQR: 14.0–26.0) and the MTX-tolerant group (median = 20.5 U/L IQR: 16.0–27.5;
p
= 0.17). MTX-intolerance was prevalent in around 60% of both boys and girls. Nine out of 50 MTX-intolerant girls had elevated ALT-levels compared to 0/22 MTX-intolerant boys, however, there was no difference in median ALT levels between the two groups. Furthermore, the MTX-intolerant girls had a higher MISS (median = 14.0 IQR: 9.3–17) than the MTX-intolerant boys (median = 10.0 IQR: 7.3–12;
p
= 0.009). Our study did not find a difference in ALT-levels between MTX-intolerant and MTX-tolerant children. However, only MTX-intolerant girls and no MTX-intolerant boys showed elevated ALT-levels.
We report a 12-week-old boy presenting with incomplete refractory Kawasaki disease (KD) complicated with macrophage activation syndrome (MAS). The infant presented with cerebral irritability, pain, ...tachypnoea and vomiting for 10 days. He did not fulfil any of the classic diagnostic criteria for KD. Pericardial effusion on echocardiography in addition to severe dilatation of the coronary arteries in combination with leucocytosis and raised acute phase reactants led to the diagnosis of incomplete KD. Treatment with intravenous immunoglobulin and aspirin was initiated but without any response. The condition was subsequently refractory to additional treatment with infliximab and high-dose methylprednisolone. His condition worsened, fulfilling the criteria for MAS. High-dose anakinra was initiated, and remission of the inflammation was achieved.
Children with rheumatic disease and compromised immune system have an increased risk of infection. Streptococcus pneumoniae is a frequent pathogen, and immunization is recommended. In this study, we ...investigated whether immunocompromised children with rheumatic disease do respond to pneumococcal immunization with 13‐valent pneumococcal conjugate vaccine followed by 23‐valent pneumococcal polysaccharide vaccine. The study was conducted at two tertiary referral hospitals in Denmark from 2015 to 2018. Patients with rheumatic disease and compromised immune system aged 2‐19 years were eligible. Patients were vaccinated with 13‐valent pneumococcal conjugate vaccine followed by 23‐valent pneumococcal polysaccharide vaccine. A blood sample was collected before vaccination and after each vaccination. IgG antibodies were quantified for twelve serotypes. Seroprotection for each serotype was defined as IgG ≥0.35 µg/mL. A total of 27 patients were enrolled. After the conjugate vaccine, an increase in antibody titres compared with pre‐vaccination was found for all serotypes and 9/12 were significant. After the polysaccharide vaccine, the antibody titres for all serotypes but one was seen to increase but none reached significance. The proportion of patients protected before immunization ranged from 20.8% to 100% for the individual serotypes. Odds ratio for achieving seroprotection after the conjugate vaccine was >1 for 10/12 serotypes but only significant for three serotypes. After the polysaccharide vaccine, the odds ratio was >1 for 9/12 serotypes but none reached significance. In conclusion, children with rheumatic disease and compromised immune system respond to pneumococcal immunization with 13‐valent pneumococcal conjugate vaccine and maintain antibody levels upon subsequent immunization with 23‐valent pneumococcal polysaccharide vaccine.
The aim of this study is to investigate whether methotrexate-induced nausea is associated with anxiety or the use of coping strategies in children with juvenile idiopathic arthritis (JIA) treated ...with methotrexate (MTX). This is an observational study of children diagnosed with JIA (ILAR criteria), treated with MTX and aged 9 years or above. MTX-induced nausea was determined by the children’s completion of a nausea diary and the parents’ completion of the Methotrexate Intolerance Severity Score (MISS). Anxiety was assessed by the Beck Youth Inventories-Anxiety Inventory (BYI-A) and coping strategies were evaluated by an adapted Nausea Coping Questionnaire. Enrolled were 121 children (82 girls: 39 boys) with a median age (IQR) of 13.3 (11.3–15.1) years. The median MTX-dose (IQR) was 9.7 (9.0–10.9) mg/m
2
/week. The median treatment duration (IQR) was 340 (142–766) days. The MISS was completed for 120 children; 77 children completed the nausea diary for at least 7 days. MTX-induced nausea was present in 61% (73/120) of the children according to the MISS and in 73% (56/77) of the children according to the nausea diary. MTX-induced nausea was associated with a more frequent use of the coping strategy internalizing/catastrophizing (MISS,
p
= 0.012; diary,
p
< 0.0001) and higher BYI-A raw scores (diary,
p
= 0.016). MTX-induced nausea was associated with anxiety and the use of coping strategies in children with JIA. These psychological factors may be part of the mechanism behind the inter-individual variation in the level of nausea to MTX treatment.
Dentofacial asymmetries are often observed in patients with juvenile idiopathic arthritis (JIA) and temporomandibular joint (TMJ) involvements. The aim of this split-face study was to associate types ...of radiologic TMJ abnormalities with the degree of dentofacial asymmetry in patients with unilateral TMJ involvements assessed with cone-beam computed tomography.
Forty-seven JIA patients and 19 nonarthritic control subjects were included in the study. Normal condylar radiologic cone-beam computed tomography appearance in at least 1 TMJ was the inclusion criterion for all patients with JIA. The contralateral TMJ was thereafter scored as either “normal,” “deformed,” or “erosive,” consistent with predefined criteria. Based on the bilateral radiologic TMJ appearances, 3 JIA groups were assigned: normal/normal, normal/deformed, and normal/erosive. The severity of the dentofacial asymmetry was compared between the JIA groups and control subjects. Dentofacial asymmetry was expressed as interside ratios and angular measurements.
Eighty-seven percent of the JIA patients were being treated or had previously received treatment with a functional orthopedic appliance at the time of the cone-beam computed tomography. Significantly greater dentofacial asymmetries were observed in the 2 groups of JIA patients with unilateral condylar abnormalities (deformation or erosion) than in the other groups. A similar degree of dentofacial asymmetry was observed in JIA patients with bilateral normal TMJs and in the nonarthritic control group.
JIA patients with unilateral condylar abnormalities (deformation or erosion) exhibited significantly more severe dentofacial asymmetries than did the JIA patients without condylar abnormalities and the control subjects. We found the same degree of dentofacial asymmetry when dividing patients with condylar abnormalities into deformation and erosion groups.
•Dentofacial asymmetries often occur in patients with juvenile idiopathic arthritis (JIA).•Dentofacial development is affected more severely in patients with condylar abnormalities.•Dysmorphic dentofacial development is not associated with a specific type of condylar abnormality.•Combined condylar deformations and erosions were observed in one third of the TMJs in JIA patients.
We present two 11-year-old girls with chronic recurrent multifocal osteomyelitis, treated with adalimumab. Both developed severe intracranial complications to sinusitis. Patient 1 had been treated ...with adalimumab for 15 months when she developed acute sinusitis complicated by an orbital abscess, forehead swelling, a subdural empyema and osteomyelitis of the frontal bone. She was treated with a rhinosurgical and neurosurgical approach with intravenous antibiotics.Patient 2 had been in adalimumab treatment for 10 weeks. Adalimumab was discontinued 8 weeks prior to developing subdural empyema and subcortical abscesses in combination with sinusitis. She was treated with endoscopic sinus surgery and intravenous antibiotics. Both patients had developed psoriasis and episodes of infection during treatment. They were non-septic and had low fever on presentation. None of the patients suffered any long-term neurological sequelae. The immunosuppressive treatment with adalimumab is considered to be the cause of the sinogenic intracranial complications in our cases.
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