To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN).
Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were ...diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, α-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-β (TGF-β), transferrin, and vitamin D binding protein (VDBP).
Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-β (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve ≥ 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups.
Low urine levels of TGF-β and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy.
PURPOSE OF REVIEWThe current review summarizes the existing knowledge about exercise therapy in the management of juvenile idiopathic arthritis (JIA) along with activity level, functional abilities ...and exercise capacity of this population.
RECENT FINDINGSCurrent studies show that children with JIA are considerably less active than their peers. They have significantly impaired aerobic and anaerobic exercise capacity. The inactivity, decreased exercise capacity and disease course lead to deconditioning and disability. Adolescent girls with polyarticular rheumatoid factor-positive subtype appear to be most vulnerable to disability. Recent trials suggest that structured aerobic training or low-intensity programs do not exacerbate arthritis and can lead to improved physical fitness, quality of life and functional abilities in children and adolescents with JIA.
SUMMARYInactivity in pediatric patients with JIA leads to deconditioning and disability and decreased bone mass, reduced quality of life and possibly increased mortality in adulthood. Although advances in pharmacology have improved the lives of children with JIA, management should also include a moderate, consistent exercise program or more active lifestyle. Physical activity may improve exercise capacity, decrease disability in adulthood, improve quality of life and, in some patients, decrease disease parameters. Further studies are needed to assess practicality of various programs and long-term effects of exercise in children and adolescents with JIA.
Anti-signal recognition particle (anti-SRP) is a myositis-specific autoantibody that is linked to a severe polymyositis (PM) associated with interstitial lung disease (ILD) and esophageal dysmotility ...in adults. We describe 3 African American adolescent girls with anti-SRP juvenile PM. One child required aggressive treatment to control her disease and 2 were refractory to multiple immunosuppressants. Patient 1 developed ILD and cardiac disease; Patient 2 developed ILD; Patient 3 developed esophageal dysmotility and cardiac disease. Organ system involvement was comparable to that seen in adults. We conclude that testing for anti-SRP in children with PM may facilitate diagnosis and management.
Abstract Background The American College of Rheumatology (ACR)/Childhood Arthritis and Rheumatology Research Alliance (CARRA) Mentoring Interest Group (AMIGO) is an inter-institutional mentorship ...program launched to target mentorship gaps within pediatric rheumatology. Initial program evaluation indicated increased mentorship access. Given the small size of the pediatric rheumatology workforce, maintaining a consistent supply of mentors was a potential threat to the longevity of the network. Our aims were to: (i) describe the sustainability of AMIGO over the period 2011–2018, (ii) highlight ongoing benefits to participants, and (iii) describe challenges in the maintenance of a mentorship network. Methods A mixed-methods approach centered on a quality improvement framework was used to report on process and outcomes measures associated with AMIGO annual cycles. Results US and Canada Pediatric rheumatology workforce surveys identified 504 possible participants during the time period. As of fall 2018, 331 unique individuals had participated in AMIGO as a mentee, mentor or both for a program response rate of 66% (331/504). Survey of mentees indicated high satisfaction with impact on general career development, research/scholarship and work-life balance. Mentors indicated increased sense of connection to the community and satisfaction with helping mentees despite limited perceived benefit to their academic portfolios. Based on AMIGO’s success, a counterpart program for adult rheumatology, Creating Adult Rheumatology Mentorship in Academia (CARMA), was launched in 2018. Conclusions Despite the challenges of a limited workforce, AMIGO continues to provide consistent access to mentorship opportunities for the pediatric rheumatology community. This experience can inform approaches to mentorship gaps in other academic subspecialties.
Methotrexate (MTX) is standard treatment in pediatric chronic anterior uveitis (CAU). Addition of tumor necrosis factor-α inhibitors (TNFi) is often needed. We describe the timing and risk factors ...for TNFi use in children with CAU on MTX.
In this retrospective study, we reviewed 51 records, and 46 met inclusion criteria. Primary outcome was the addition of TNFi due to active CAU per Standardization of Uveitis Nomenclature criteria. Time to TNFi and factors associated with their addition were assessed using survival analysis models.
Of 46 children treated with MTX for uveitis (36 juvenile idiopathic arthritis-associated uveitis, 10 idiopathic CAU), 72% had ocular complications. MTX was started a median of 5.0 months, and TNFi 43 months from uveitis diagnosis. Kaplan-Meier estimates suggest that cumulatively, 12% (95% CI: 4-23%) start TNFi within 6 months of MTX, 21% (12-37%) within 1 year, and 39% (24-54%) within 2 years. On Cox Proportional Hazard regression analysis, children with idiopathic CAU required TNFi earlier in their uveitis course (at 3 months (Hazard Ratio 6.06; 95% confidence interval (1.25-29.41))). Females appeared less likely to require TNFi early. Children treated in 2012 and later were more likely to receive TNFi earlier than those treated before 2012.
Little is known about optimal time to initiate treatment or factors associated with the need to add TNFi in children on MTX. Children with idiopathic CAU and males required TNFi earlier in their course. Factors associated with these potential risk factors for TNFi warrant further investigation.
Objective
To create a pediatric rheumatology Top 5 list as part of the American Board of Internal Medicine Foundation's Choosing Wisely campaign.
Methods
Delphi surveys of a core group of ...representative pediatric rheumatology providers from across North America generated candidate Top 5 items. Items with high content agreement and perceived to be of prevalent use and of high impact were included in a survey of all American College of Rheumatology (ACR) members who identified themselves as providing care to pediatric patients. Items with the highest ratings were subjected to literature review and further evaluation.
Results
A total of 121 candidate items were proposed in the initial Delphi survey and were reduced to 28 items in subsequent surveys. These 28 items were sent to 1,198 rheumatology providers who care for pediatric patients, and 397 (33%) responded. Based upon survey data and literature review, the Top 5 items were identified. These items focused on testing for antinuclear antibodies, autoantibody panels, Lyme disease, methotrexate toxicity monitoring, and use of routine radiographs.
Conclusion
The ACR pediatric rheumatology Top 5 is one of the first pediatric subspecialty–specific Choosing Wisely Top 5 lists and provides an opportunity for patients and providers to discuss appropriate use of health care in pediatric rheumatology.
Rheumatoid factor-positive polyarthritis (RF+ poly) is the juvenile idiopathic arthritis (JIA) category that resembles adult seropositive rheumatoid arthritis (RA). We studied children with RF+ ...and/or anticyclic citrullinated peptide antibody (anti-CCP)+ JIA to determine what proportion of those children meet International League of Associations for Rheumatology (ILAR) criteria for RF+ poly JIA and to assess for significant differences between children who meet RF+ poly criteria and those who are classified in other categories.
Charts of children with JIA who were RF+ and/or anti-CCP+ were reviewed. Children with RF+ poly JIA were compared to children in other categories. Statistical analysis was performed using chi-square, Fisher's exact test, and the Student's t-test.
Of 56 children with RF+ and/or anti-CCP+ JIA, 34 (61%) met ILAR criteria for RF+ poly JIA. Twelve children had RF-/anti-CCP+ JIA with low anti-CCP titers. When these 12 children were excluded, there were few significant differences between children who met criteria for RF+ poly and those who were classified in other categories. The American College of Rheumatology/European League Against Rheumatism criteria for RA identified more RF+ children than did the ILAR RF+ poly classification (100% vs 77%).
A number of children with RF+ arthritis were excluded from the RF+ poly JIA classification, though many demographic features and disease measures were similar to those of children who met criteria for RF+ poly JIA. We propose prioritization of RF/anti-CCP positivity over specific exclusions, along with inclusion of anti-CCP, in future revisions of the JIA classification criteria, to improve the sensitivity of diagnosing childhood-onset RA.
The association between rheumatoid arthritis (RA) and periodontitis is well established. Some children with juvenile idiopathic arthritis (JIA) phenotypically resemble adults with RA, characterized ...by the presence of anti-cyclic citrullinated peptide (CCP) antibodies. We sought to investigate an association between CCP-positive JIA and symptoms of periodontitis and antibodies to oral microbiota.
Antibodies to oral pathogens Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum were measured using ELISA in 71 children with CCP-positive JIA and 74 children with CCP-negative JIA. Oral health history was collected from 37 children with CCP-positive JIA and 121 children with CCP-negative JIA. T-tests, Chi-square tests, Mann-Whitney U tests, and multivariable regression were used to compare the groups.
Compared to those with CCP-negative JIA, children with CCP-positive JIA were more likely to be female, older and non-Caucasian. Anti-P. gingivalis (p <0.003) and anti-P. intermedia (p <0.008) IgG antibody titers were higher in the CCP-positive cohort. Differences in P. gingivalis antibody titers remained significant after adjusting for age (p = 0.007). Children with CCP-positive JIA more likely reported tender/bleeding gums (43 % vs. 24 %, p < 0.02) compared to children with CCP-negative JIA. After controlling for age at collection, the odds of having tender/bleeding gums were 2.2 times higher in the CCP-positive group compared (95 % CI 0.98 - 4.83; p = 0.056).
Children with CCP-positive JIA have higher antibody titers to P. gingivalis and more symptoms of poor oral health, supporting a possible role for periodontitis in the etiology of CCP-positive JIA.
Multisystem inflammatory syndrome in children (MIS-C) can cause a myriad of cardiac manifestations, including coronary dilation and aneurysms; giant aneurysms are infrequent. We describe 3patients ...with giant coronary aneurysms associated with MIS-C, including the youngest case reported to date, treated with intravenous immunoglobulin, corticosteroids, and biologic agents. (
Level of Difficulty: Intermediate.
)
Biologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many ...patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown.
We interrogated the circulatory reservoir of CD4
immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString.
An inflammatory memory subset of CD3
CD4
CD45RA
TNFα
T cells deficient in immune checkpoints (PD1
CD152
) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling.
A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.
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