Andrew Lasky

Development of consensus treatment plans for juvenile localized scleroderma: A roadmap toward comparative effectiveness studies in juvenile localized scleroderma

Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS.

The effect of genotype on methotrexate polyglutamate variability in juvenile idiopathic arthritis and association with drug response

OBJECTIVE The response to and toxicity of methotrexate (MTX) are unpredictable in patients with juvenile idiopathic arthritis (JIA). Intracellular polyglutamation of MTX, assessed by measuring concentrations of MTX polyglutamates (MTXGlu), has been demonstrated to be a promising predictor of drug response. Therefore, this study was aimed at investigating the genetic predictors of MTXGlu variability and associations between MTXGlu and drug response in JIA. METHODS The study was designed as a single-center cross-sectional analysis of patients with JIA who were receiving stable doses of MTX at a tertiary care childrens hospital. After informed consent was obtained from the 104 patients with JIA, blood was withdrawn during routine MTX-screening laboratory testing. Clinical data were collected by chart review. Genotyping for 34 single-nucleotide polymorphisms (SNPs) in 18 genes within the MTX metabolic pathway was performed. An ion-pair chromatographic procedure with mass spectrometric detection was used to measure MTXGlu1-7. RESULTS Analysis and genotyping of MTXGlu was completed in the 104 patients. K-means clustering resulted in 3 distinct patterns of MTX polyglutamation. Cluster 1 had low red blood cell (RBC) MTXGlu concentrations, cluster 2 had moderately high RBC MTXGlu1+2 concentrations, and cluster 3 had high concentrations of MTXGlu, specifically MTXGlu3-5. SNPs in the purine and pyrimidine synthesis pathways, as well as the adenosine pathway, were significantly associated with cluster subtype. The cluster with high concentrations of MTXGlu3-5 was associated with elevated liver enzyme levels on liver function tests (LFTs), and there were higher concentrations of MTXGlu3-5 in children who reported gastrointestinal side effects and had abnormal findings on LFTs. No association was noted between MTXGlu and active arthritis. CONCLUSION MTXGlu remains a potentially useful tool for determining outcomes in patients with JIA being treated with MTX. The genetic predictors of MTXGlu variability may also contribute to a better understanding of the intracellular biotransformation of MTX in these patients.

Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

OBJECTIVE Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. METHODS Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. RESULTS Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). CONCLUSION In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5).

Red blood cell folate concentrations and polyglutamate distribution in juvenile arthritis: predictors of folate variability.

Objective Methotrexate (MTX) has several enzymatic targets in the folate pathway. To better understand the variability in response to MTX, we characterized the interindividual variability of intracellular folate pools in children with juvenile arthritis (JA) and determined clinical and genetic contributors to this variability. Study design This exploratory single-center cross-sectional study evaluated 93 patients with JA not currently receiving MTX. Whole blood, plasma, and erythrocyte folate concentrations were determined after deconjugation and analyzed through reversed-phase separation and stable isotope dilution tandem mass spectrometry. Folate polyglutamates were measured in red blood cell lysates using an ion-pair reversed phase chromatography tandem mass spectrometry method. Results Intracellular concentrations of 5-methyl-tetrahydrofolate (5-CH3-THF) and 5,10-methenyl-tetrahydrofolate varied approximately 20-fold and 80-fold, respectively. The polyglutamated forms of 5-CH3-THF as a percentage of total 5-CH3-THF (5-CH3-THFGlun) were also measured. Hierarchical clustering of 5-CH3-THFGlun revealed two groups, each with two distinct clusters. There was an inverse relationship between 5-CH3-THFGlun chain length and plasma 5-CH3-THF concentrations. A subgroup of patients with a historical intolerance to MTX had significantly lower cellular folate concentrations (P<0.0001). In univariate analyses, clinical variables including sex, age, and folate supplementation in addition to variations in MTHFR, MTR, and SLC25A32 were associated with differential intracellular folate redox concentrations. Multivariate analysis further supported the association of single nucleotide polymorphisms in SLC25A32, MTHFR, and MTR with variability in intracellular 5-CH3-THF and 5,10-methenyl-tetrahydrofolate concentrations, respectively. Conclusion Measurement of intracellular folate isoforms may contribute toward a better understanding of individual MTX effects in JA. Clinical variables in addition to genotypic differences beyond MTHFR may additionally explain differential intracellular folate concentrations and variable responses to MTX.

Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for juvenile idiopathic arthritis-associated and idiopathic chronic anterior uveitis

Systemic immunosuppressive treatment of pediatric chronic anterior uveitis (CAU), both juvenile idiopathic arthritis–associated and idiopathic anterior uveitis, varies, making it difficult to identify best treatments. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for CAU for the purpose of reducing practice variability and allowing future comparison of treatments using comparative effectiveness analysis techniques.

Difficult Discharge in Pediatric Rehabilitation Medicine Causing Moral Distress

ABSTRACT An ethical dimension exists in nearly all decisions made. Yet, there are clinical decisions in which the ethical dilemma is so difficult for the clinician that it results in moral distress. We present one example of a morally distressing situation in which care was provided for a child who had altered physical abilities after a trauma and was being discharged to a suboptimal family environment. Caring for a child with an acquired spinal cord injury requires significant resources. When a family is able to physically care for the child, but has demonstrated incomplete follow-through, the team is at risk for experiencing significant moral distress.

Retinal Involvement in Patients with Juvenile Dermatomyositis

The authors describe the clinical presentations and ophthalmic findings of two patients with juvenile dermatomyositis. The results of their dilated eye examinations proved to influence the treatment of the disease process because retinal pathology was used as a factor to escalate the degree of anti-inflammatory therapy. Therefore, an initial ophthalmic examination may be considered in patients with new-onset juvenile dermatomyositis.

Comparison of idiopathic and secondary uveitis patients seen in a dual pediatric rheumatology-ophthalmology clinic

Purpose Uveitis is an intraocular inflammatory disease that accounts for 10-15% of all cases of total blindness in the U.S. Although uveitis is more prevalent in adults, children comprise approximately 5% of the uveitis population. The most common etiologies of childhood uveitis are idiopathic, infectious, and rheumatologic. Idiopathic uveitis is the most common cause of pediatric uveitis, while uveitis associated with Juvenile Idiopathic Arthritis (JIA) is the most common secondary cause. In 2005, the physicians of Children’s Mercy’s Hospital created a dual Pediatric Rheumatology and Ophthalmology uveitis clinic for patients with ocular inflammation requiring systemic immunosuppressant therapy. An ophthalmologist and rheumatologist jointly evaluate each patient, and formulate a comprehensive plan with the patient and family. To our knowledge, this is the only pediatric uveitis clinic in the U.S. staffed by the two subspecialties simultaneously. The aim of this study was to determine if the characteristics of ocular involvement differ between severe Idiopathic uveitis (IU) and Secondary uveitis (SU).

Intracellular folate concentrations in Down syndrome patients with arthritis

Purpose Patients with Down syndrome (DS) have an increased prevalence of arthritis compared to the general population, and often the arthritis is severe and debilitating. In light of the concern for folate deficiency in this patient population, and a clinically observed increased risk for methotrexate (MTX) toxicity, we investigated intracellular folate concentrations in DS patients on methotrexate therapy.

Developing juvenile localized scleroderma (jLS) consensus treatment regimens for comparative effectiveness studies.

Purpose LS can cause significant morbidity in the growing child, including joint contractures and facial and extremity hemiatrophy. Optimal therapy is not known, and few randomized clinical trials have been carried out. A prior survey of Childhood Arthritis and Rheumatology Research Alliance (CARRA) members identified methotrexate (MTX) and corticosteroids (CS) as the most commonly used medications to treat serious jLS. However, there was no consensus on dose, route of administration, or duration of treatment for these medications. Objective: To develop standardized consensus treatment regimens and disease assessments tools for jLS.