Systemic lupus erythematosus (SLE) is a complex autoimmune disease and occurs worldwide in both children and adults. The estimated annual incidence among children is 2.22/100,000 and among adults is ...23.2/100,000 in the United States. There is increasing understanding about differences in disease manifestations, medication use, and disease severity between those with childhood-onset SLE as compared with adult-onset SLE. Children have a more fulminant disease onset and course than adults with SLE, resulting in two to three times higher mortality. In future years, we anticipate more insight into the genetics between childhood-onset SLE and adult-onset SLE to help delineate the best therapies for both subsets of patients.
This review will provide updates in the outcomes in the common rheumatologic diseases with kidney involvement. Covered are also advances in therapeutics for the use of pediatric rheumatologic ...diseases with kidney involvement, as well as the potential kidney complications from other rheumatologic diseases and their medications.
Two of the more common rheumatologic diseases with kidney involvement, lupus and vasculitis, continue to show inadequate response to initial therapy of renal disease and practice continues to be driven by results of adult studies.
There is a continued need for pediatric specific studies in rheumatologic diseases with kidney involvement as outcomes continue to be inadequate. Despite recently approved treatments for adults with rheumatic diseases and kidney involvement, therapeutic options in pediatrics remain limited, contributing to the overall morbidity and mortality.
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect almost any organ in the human body. Despite significant advancements in our understanding of SLE over the recent years, its ...exact mode of onset and disease progression remains elusive. Low concordance rates among monozygotic twins with SLE (as low as 24%), clustering of disease prevalence around polluted regions and an urban–rural difference in prevalence all highlight the importance of environmental influences in SLE. Experimental data strongly suggests a complex interaction between the exposome (or environmental influences) and genome (genetic material) to produce epigenetic changes (epigenome) that can alter the expression of genetic material and lead to development of disease in the susceptible individual. In this review, we focus on the available literature to explore the role of environmental factors in SLE disease onset and progression and to better understand the role of exposome–epigenome–genome interactions in this dreaded disease.
Objective
Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to ...describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA‐LD).
Methods
Clinical data collected since 2010 were ed from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed.
Results
Eighteen patients with SJIA‐LD were identified. Radiographic findings included diffuse ground‐glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA‐LD were younger at the diagnosis of systemic JIA (odds ratio OR 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin‐18 (IL‐18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA‐LD lacked genetic, serologic, or functional evidence of granulocyte–macrophage colony‐stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA‐LD rarely demonstrated proteinaceous material and had less lipid‐laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA‐LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA‐LD contained elevated levels of IL‐18 and the interferon‐γ–induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA‐LD identified up‐regulated type II interferon and T cell activation networks. This signature was also present in SJIA‐LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA‐LD.
Conclusion
Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.
In a randomized trial involving children with severe systemic juvenile idiopathic arthritis, the anti–interleukin-6 receptor antibody tocilizumab was effective (response rate, 85% with tocilizumab ...vs. 24% with placebo). Adverse events included serious infections and neutropenia.
Systemic juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis, systemic manifestations (spiking fever, rash, hepatosplenomegaly, lymphadenopathy, and serositis), and substantially elevated inflammatory markers.
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It is the most severe subtype of JIA; approximately half the patients have an unremitting course of chronic polyarthritis (with or without persistent systemic features). Substantial joint damage and disability often develop in these patients.
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Treatment remains challenging because of the limited efficacy of methotrexate
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and tumor necrosis factor inhibitors
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and because of the major toxicity of high-dose glucocorticoids. Efficacy of the interleukin-1 inhibitor anakinra has been reported in a subset of patients.
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Objective
To compare the diagnostic usefulness of the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for systemic lupus erythematosus ...(SLE) to that of the 1997 ACR classification criteria for SLE when applied to youths (age ≤21 years) with SLE.
Methods
Data were extracted from electronic health records of patients followed at a large academic pediatric hospital. The treating rheumatologist’s diagnosis of SLE served as the standard criterion for identifying SLE patients (cases). Controls were patients with juvenile dermatomyositis (DM), juvenile scleroderma, or juvenile systemic sclerosis (SSc). The 2019 EULAR/ACR criteria and the 1997 ACR criteria were tested against the standard criterion.
Results
A total of 112 SLE patients ages 2–21 years and 105 controls ages 1–19 years (66% juvenile DM, 34% juvenile scleroderma or juvenile SSc) were available for analysis. The 2019 EULAR/ACR criteria had significantly higher sensitivity (85% versus 72%; P = 0.023) and similar specificity (83% versus 87%; P = 0.456) than the 1997 ACR criteria. The mean ± SD 2019 EULAR/ACR classification summary scores were significantly higher among non‐White than White patients (22.41 ± 10.04 versus 17.59 ± 9.19; P < 0.01). The sensitivity of the 2019 EULAR/ACR criteria in non‐White/White patients was 92%/80% (P = 0.08) versus 83%/64% (P < 0.02) for the 1997 ACR criteria. The sensitivity of the 2019 EULAR/ACR criteria was not affected by age or sex.
Conclusion
The 2019 EULAR/ACR criteria efficiently classify youths with SLE, irrespective of age, sex, and race. Compared to the 1997 ACR criteria, the new criteria are significantly more sensitive and similarly specific in youths with SLE.
Some complement deficiencies predispose to systemic lupus erythematosus (SLE) early in life. Currently, there are no known unique physiologic or genetic pathways that can explain the variability in ...disease phenotypes. Children present with more acute illness and have more frequent renal, hematologic, and central nervous system involvement compared to adults with SLE. Almost all children require corticosteroids during the course of their disease; many are treated with immunosuppressive drugs. Mortality rates remain higher with pediatric SLE. Children and adolescents accrue more damage, especially in the renal, ocular and musculoskeletal organ systems. Conversely, cardiovascular mortality is more prevalent in adults with SLE.
PURPOSE OF REVIEWProvide an update of studies published in last 2 years on the outcomes and therapies in childhood-onset systemic lupus erythematous (cSLE).
RECENT FINDINGSAdditional evidence has ...been provided about the benefits of universal hydroxychloroquine in SLE patients, although antimalarial maculopathy may be more prevalent than previously thought. Recent studies support lower glucocorticoid doses than used in the past may provide comparable therapeutic benefits, and cSLE patients can mount adequate immunogenic response and sustain long-term seroprotective titers when vaccinated. Long-term studies of adults with cSLE confirmed that damage accrual increases with disease duration. Cardiovascular disease, renal transplants, replacement arthroplasties, and myocardial infarctions occur between 20 and 40 years of age. Higher prednisone doses predicted higher damage trajectory and antimalarial exposure was protective. There were no prospective clinical trials published in pediatric patients with cSLE, but positive results from phase II trials with bariticinib and ustekinumab in adult SLE may raise the expectation that these drugs could be beneficial when used in cSLE.
SUMMARYThe dire need for more clinical trials and licensed medications for cSLE persist as well as decreasing damage accrual.
Objective
To propose a common nomenclature to refer to individuals who fulfill the American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) during childhood or ...adolescence.
Methods
The medical literature was reviewed for studies conducted in the target population between 1960 and December 2011 to obtain information about the terms used to refer to such children and adolescents. We reviewed the threshold ages used and disease features considered to discriminate these individuals from patients with onset of SLE during adulthood. Furthermore, the nomenclature used in other chronic diseases with onset during both childhood and adulthood was assessed.
Results
There was an astonishing variability in the age cutoffs used to define SLE onset prior to adulthood, ranging from 14–21 years, but most studies used age 18 years. The principal synonyms in the medical literature were SLE without reference to the age at onset of disease, childhood‐onset SLE, juvenile SLE, and pediatric (or paediatric) SLE.
Conclusion
Based on the definition of childhood, in analogy with other complex chronic diseases commencing prior to adulthood, and given the current absence of definite genetic variations that discriminate adults from children, the term childhood‐onset SLE is proposed when referring to individuals with onset of SLE prior to age 18 years.
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