Safety updates in novel therapeutics for pediatric rheumatic disease.

PURPOSE OF REVIEW: Biologics and novel targeted therapeutics have transformed the management of pediatric rheumatic diseases over the past two decades; however, questions about short-term and long-term safety remain. Safety data gathered from recent clinical trials, long-term extensions of prior trials, registries, and other real-world evidence are summarized here for biologics and novel therapeutics commonly prescribed for pediatric rheumatic diseases. RECENT FINDINGS: With nearly 20 years of therapeutic experience, tumor necrosis inhibitors (TNFi) are generally well tolerated, although infections, malignancy, and development of new autoimmunity remain a concern. Risk of infections may be higher in IL-1 and IL-6 inhibitors, and lower in abatacept, compared with TNFi. Safety data for B-cell-targeted therapeutics and janus kinase inhibitors are emerging, but remain limited, especially in children. SUMMARY: Biologic and novel targeted therapeutics offer a promising future for children with pediatric rheumatic disease. However, long-term safety data in children remain limited for several agents. With any therapeutic option, both short-term and long-term safety concerns must be weighed against individual clinical needs when choosing the optimal treatment for each child.

Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study.

BACKGROUND: Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. METHODS: In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. RESULTS: IFX trough concentrations ranged from 0 to > 40 µg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. CONCLUSIONS: Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

Distinguishing Blau Syndrome from Systemic Sarcoidosis.

PURPOSE OF REVIEW: The purpose of this review is to provide a framework to distinguish Blau syndrome/Early Onset Sarcoidosis and Sarcoidosis clinically. We also discuss relevant differences in genetics, pathogenesis, and management of these diseases. RECENT FINDINGS: Blau syndrome and Sarcoidosis share the characteristic histologic finding of noncaseating granulomas as well as some similar clinical characteristics; nevertheless, they are distinct entities with important differences between them. Blau syndrome and Early Onset Sarcoidosis are due to one of numerous possible gain-of-function mutations in NOD2, commonly presenting before age 5 with a triad of skin rash, arthritis, and uveitis. However, as more cases are reported, expanded clinical manifestations have been described. In systemic Sarcoidosis, there are numerous susceptibility genes that have been identified, and disease is thought to result from an environmental exposure in a genetically susceptible host. It most often presents with constitutional symptoms and pulmonary involvement and typically affects adolescents and adults. This paper reviews the similarities and differences between Blau syndrome and Sarcoidosis. We also discuss the importance of distinguishing between them, particularly with regard to prognosis and outcomes.

Altered Folate Homeostasis in Children with Down Syndrome: A Potential Basis for Enhanced Methotrexate Toxicity.

Methotrexate is used to treat autoimmune and oncologic diseases in children with Down syndrome. However, increased methotrexate-related toxicity is reported in this population. We evaluated differences in the concentrations and distribution of erythrocyte folates in children with Down syndrome as a potential basis for this enhanced toxicity.

Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients.

OBJECTIVE: Variants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high-dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low-dose MTX in juvenile idiopathic arthritis (JIA) patients. METHODS: The study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow-up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate. RESULTS: The SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392). CONCLUSION: SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high-dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis.

OBJECTIVE: To develop treatment recommendations for children with juvenile idiopathic arthritis manifesting as non-systemic polyarthritis, sacroiliitis, or enthesitis. METHODS: The Patient/Population, Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by members of the guideline development teams. A systematic review was conducted to compile evidence for the benefits and harms associated with treatments for these conditions. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of evidence. A group consensus process was conducted among the Voting Panel to generate the final recommendations and grade their strength. A Parent and Patient Panel used a similar consensus approach to provide patient/caregiver preferences for key questions. RESULTS: Thirty-nine recommendations were developed (8 strong and 31 conditional). The quality of supporting evidence was very low or low for 90% of the recommendations. Recommendations are provided for the use of nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, biologics, and intraarticular and oral glucocorticoids. Recommendations for the use of physical and occupational therapy are also provided. Specific recommendations for polyarthritis address general medication use, initial and subsequent treatment, and adjunctive therapies. Good disease control, with therapeutic escalation to achieve low disease activity, was recommended. The sacroiliitis and enthesitis recommendations primarily address initial therapy and adjunctive therapies. CONCLUSION: This guideline provides direction for clinicians, caregivers, and patients making treatment decisions. Clinicians, caregivers, and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP.

Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis. Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX; however, the mechanism of this interaction has yet to be defined. Therefore, in this study, we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells. Small interfering RNA-based silencing of NAMPT expression resulted in a greater than 3-fold increase in sensitivity to MTX (P < 0.005) that was completely reversed by supplementation with folinic acid. Despite a 68% reduction in cellular NAD levels in NAMPT-deficient cells, no change in expression or activity of dihydrofolate reductase was observed and uptake of MTX was not significantly altered. MTX did not potentiate the depletion of cellular NAD levels, but NAMPT-deficient cells had significant elevations in levels of intermediates of de novo purine biosynthesis and were 4-fold more sensitive to depletion of ATP by MTX (P < 0.005). Supplementation with hypoxanthine and thymidine completely reversed the antiproliferative activity of MTX in NAMPT-deficient cells and corresponded to repletion of the cellular ATP pool without any effect on NAD levels. Together, these findings demonstrate that increased MTX activity with decreased NAMPT expression is dependent on the antifolate activity of MTX and is driven by enhanced sensitivity to the ATP-depleting effects of MTX. For the first time, these findings provide mechanistic details to explain the increase in pharmacological activity of MTX under conditions of reduced NAMPT activity.

Cytokine Biomarkers of Disease Activity and Therapeutic Response after Initiating Methotrexate Therapy in Patients with Juvenile Idiopathic Arthritis.

STUDY OBJECTIVE: To evaluate the relationship between plasma cytokine levels with disease activity and therapeutic response in patients with juvenile idiopathic arthritis (JIA) after initiating methotrexate (MTX) therapy. DESIGN: Single-center observational prospective cohort study. SETTING: Outpatient pediatric rheumatology clinic at a tertiary care academic pediatric hospital. PATIENTS: The study included 61 patients diagnosed with JIA who started therapy with standard-dose MTX 15 mg/m2 /week. At 3 months, treating physicians were given the option of maintaining the MTX dose, increasing the MTX dose, or adding etanercept (ETN), based on their clinical judgment. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated at baseline, 3 months (51 patients), and 6 months (35 patients). Plasma samples from each visit were analyzed for interleukin (IL)-1α, IL-1ß, IL-1Ra, IL-6, and tumor necrosis factor-α (TNF-α). Cytokine concentrations were evaluated for relationships with disease activity using the 71-joint count Juvenile Arthritis Disease Activity Score (JADAS). Therapeutic response was assessed by changes in JADAS. Failure to respond to standard-dose MTX was defined as the need for the addition of ETN or a MTX dose increase at or before the 3-month visit. Increased disease severity at baseline was associated with increased IL-6 (p=0.01) and TNF-α (p=0.008) levels. Initiation of MTX was associated with reductions in IL-1α (p=0.009), IL-1ß (p=0.01), IL-1Ra (p=0.007), and IL-6 (p=0.03) levels; however, reductions in JADAS were only associated with reductions in IL-6 (p=0.009) and TNF-α levels (p=0.02). Compared with responders, patients failing to respond to standard-dose MTX had increased TNF-α levels at baseline (p=0.02) and at 3 months (p=0.005). Reductions in JADAS by 6 months were observed following either the addition of ETN (p=0.009) or an increase in MTX dose (p=0.007), but the addition of ETN was associated with a median 7-fold increase in TNF-α levels (p=0.003) that corresponded with clinical response. CONCLUSION: Plasma cytokine levels were responsive to MTX therapy in patients with JIA, but only TNF-α and IL-6 levels were consistently associated with disease activity and therapeutic response. Increased TNF-α levels at baseline were associated with failure to respond to standard-dose MTX and the need for more aggressive drug therapy. Initiation of ETN resulted in increased TNF-α levels that corresponded with therapeutic response, suggesting a potential clinical benefit of monitoring TNF-α levels as a pharmacodynamic marker of etanercept activity.

Therapeutic advancements in juvenile idiopathic arthritis.

The treatment of juvenile idiopathic arthritis (JIA) has substantially evolved over the past two decades. Research has been conducted and is ongoing on how therapies can best be utilized either as monotherapy or in combination for enhanced efficacy. The introduction of biologic therapies that selectively target specific cytokines has changed the acceptable clinical course of childhood arthritis. In addition to the development and utilization of new therapeutic agents, the pediatric rheumatology community has made vital progress toward defining disease activity, developing validated outcome measures, and establishing collaborative networks to assess both clinical outcomes and the long-term side effects related to therapeutics for juvenile arthritis. In this chapter, we will discuss the therapeutic evolution in JIA over the past two decades. Although the largest strides have been made with biologic agents, and these newer drugs have more rigorous data to support their use, select commonly used non-biologic therapies are included, with the discussion focused on more recent updated literature.

Combined meta-analysis of systemic effects of allogeneic stem cell transplantation and systemic sclerosis.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a major factor of morbidity and mortality for allogeneic stem cell transplantation (aSCT). The skin and internal organ involvement is the most common systemic complication of cGVHD and closely resembles systemic sclerosis (SSc). Circulating lymphocytes characterize the autoimmune nature of both conditions. Therefore we hypothesized that the common clinical manifestation (systemic organ and skin injury) and the common underlying players (lymphocytes) justify the combined meta-analysis of these diseases. RESULTS: The aSCT and SSc datasets were uploaded from Gene Expression Omnibus (GEO), a public functional genomics data repository. The available microarray studies of peripheral blood mononuclear cells (PBMCs) and isolated lymphocytes were limited to well established microarray platforms (Affymetrix, Agilent, Canvac, and Illumina) and experimental settings with ≥10 patients per group. The resulting pools of data were merged by unique gene identifier and analyzed by the expression genome-wide association studies (eGWAS) coupled with the subtraction of the cGVHD+ and cGVHD- molecular signatures. The eGWAS was applied to 47 and 50 lymphocyte profiles from aSCT and SSc patients, respectively. The identified 35 candidates were represented by 8 known cGVHD genes (including CXCR4, LTBR and PML) and 28 new candidate genes (including SEPX1 and DNJGB1). The further mutual subtraction of cGVHD+ and cGVHD- candidates and pathway analysis identified a list of 25 genes. Seven of these genes belong to the fibroblast development and function pathway, consisting of the well known cGVHD genes CCND1, JUN, and FOS, and the new molecular targets MMP2, FOSB, TNFAIP8, and DUSP1. These genes become primary candidates for a potential link of systemic effects of cGVHD and SSc. CONCLUSIONS: We designed a new approach for meta-analysis by combining data from different diseases using common clinical manifestation as a linker. This allowed us to power up the insufficient standalone meta-analysis of aSCT microarray studies, by adding SSc samples to the data pool. This new method has successfully identified novel molecular targets for systemic effects of both aSCT and SSc. We believe that this approach is generalizable and can be applied to an array of diseases with common clinical manifestations.

Clinical characteristics of children with juvenile dermatomyositis: the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: To investigate aspects of juvenile dermatomyositis (DM), including disease characteristics and treatment, through a national multicenter registry. METHODS: Subjects meeting the modified Bohan and Peter criteria for definite juvenile DM were analyzed from the cross-sectional Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between 2010 and 2012 from 55 US pediatric rheumatology centers. Demographics, disease characteristics, diagnostic assessments, and medication exposure data were collected at enrollment. RESULTS: A total of 384 subjects met the criteria for analysis. At enrollment, the median Childhood Myositis Assessment Scale score was 51 (interquartile range [IQR] 46-52), the median Childhood Health Assessment Questionnaire score was 0 (IQR 0-0.5), and the median physician and subject global assessment scores were 1 (IQR 0-2) and 1 (IQR 0-3), respectively, out of a maximum of 10. Of the diagnostic assessments, magnetic resonance imaging was more likely than electromyography or muscle biopsy to show abnormalities. A total of 329 subjects had ≥2 diagnostic studies performed, and >34% of these subjects reported ≥1 negative study. Ninety-five percent had been treated with corticosteroids and 92% with methotrexate, suggesting that these medications were almost universally prescribed for juvenile DM in the US. CONCLUSION: In 2 years, the ongoing CARRA Registry has collected clinical data on 384 children with juvenile DM and has the potential to become one of the largest juvenile DM cohorts in the world. More research is needed about prognostic factors in juvenile DM, and differences in therapy based on manifestations of disease need to be explored by practitioners. This registry provides the infrastructure needed to advance clinical and translational research and represents a major step toward improving outcomes of children with juvenile DM.

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 children's 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.

Interstitial pneumonitis in Blau syndrome with documented mutation in CARD15.

This is the first report of a CARD15 mutation-positive patient with Blau syndrome who exhibited interstitial lung disease, a feature historically considered absent from Blau syndrome, while typical of the adult form of sarcoidosis. This case illustrates the continued evolution of the phenotype of a disease initially conceived as a familial inflammatory granulomatous disease limited to the triad of synovitis, dermatitis, and uveitis.

Blau syndrome and related genetic disorders causing childhood arthritis.

Blau Syndrome (BS) is an inheritable disorder characterized by granulomatous polyarthritis, panuveitis, and exanthema. It was described by Edward Blau in 1985, the same year in which Douglas Jabs reported a very similar family. Clinically indistinguishable from early onset sarcoidosis (EOS), both are now known to share a mutated form of caspase recruitment domain-15 (CARD 15), a protein involved in activation of nuclear factor kappa B which is in turn an up-regulator of pro-inflammatory cytokine transcription. An association between BS and EOS was suspected for years given the striking similarities of the core triad (arthritis-uveitis-dermatitis) and a common emerging pattern of systemic involvement. Hence, the familial form (BS) and the sporadic form (EOS) are almost certainly the same illness/defect, inherited in the first and acquired in the second as a result in most cases of a de novo mutation. Another form of granulomatous arthritis with uveitis, Crohn's disease, has also been associated with mutations in CARD 15 (albeit at a different domain) and despite similar phenotypes there are obvious differences including gut inflammation and pyoderma gangrenosum in Crohn's disease. This paper will review the clinical characteristics of these three disorders and their association with mutations in the CARD 15 gene.