Purpose of Review
Juvenile-onset systemic lupus erythematosus ((j)SLE) is an autoimmune/inflammatory disease that results in significant damage and disability. When compared to patients with disease ...onset in adulthood, jSLE patients exhibit increased disease activity, damage and require more aggressive treatments. This manuscript summarises age-specific pathogenic mechanisms and underscores the need for age group–specific research, classification and treatment.
Recent Findings
Genetic factors play a significant role in the pathophysiology of jSLE, as > 7% of patients develop disease as a result of single gene mutations. Remaining patients carry genetic variants that are necessary for disease development, but require additional factors. Increased ‘genetic impact’ likely contributes to earlier disease onset and more severe phenotypes. Epigenetic events have only recently started to be addressed in jSLE, and add to the list of pathogenic mechanisms that may serve as biomarkers and/or treatment targets. To allow meaningful and patient-oriented paediatric research, age-specific classification criteria and treatment targets require to be defined as currently available tools established for adult-onset SLE have limitations in the paediatric cohort.
Summary
Significant progress has been made in understanding the pathophysiology of jSLE. Meaningful laboratory and clinical research can only be performed using age group–specific tools, classification criteria and treatment targets.
Abstract The IL-10 cytokine family has nine members, four of which are located in the IL10 cluster on chromosome 1q32. These cytokines are the immune regulatory cytokine IL-10 itself, and the IL-20 ...subfamily members IL-19, IL-20, and IL-24. IL-10 instructs innate and adaptive immune responses and limits pro-inflammatory responses in order to prevent tissue damage. The IL-20 subfamily members are involved in host defense mechanisms, particularly from epithelial cells and seem essential for tissue integrity. Dysregulation of IL-10 family cytokines results in inflammation and autoimmune disease. Here, we discuss cellular source, gene regulation, and receptor complexes of cytokines in the IL10 cluster and their contribution to autoimmune disease and tissue damage.
Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The ...pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion.
Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting.
Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments.
The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.
Abstract The autoimmune/inflammatory disorder psoriasis is characterized by keratinocyte proliferation and immune cell infiltration of the skin. TCR+ CD3+ CD4− CD8− “double negative” (DN) T cells can ...derive from CD8+ T cells through the down-regulation of CD8. The inhibitory molecule programmed death (PD-)1 is expressed on activated T cells and plays a role in the maintenance of peripheral tolerance. A subset of DN T cells, characterized by the expression of PD-1, has recently been demonstrated to be self-reactive. We demonstrate that a majority of DN T cells exhibits effector memory phenotypes, express IFN-γ, and fail to proliferate. DN T cells from psoriasis patients are characterized by reduced DNA methylation of the IFNG gene and increased PD-1 expression. Furthermore, PD-1 positive DN T cells infiltrate the epidermis in psoriatic skin lesions. Our observations offer additional insight into the molecular pathophysiology of plaque psoriasis and show promise as potential disease biomarkers and/or therapeutic targets for future interventions.
Systemic Lupus Erythematosus (SLE) is an autoimmune multisystem disease with a variable clinical phenotype and no single clinical, laboratory or pathological feature that can be used as a gold ...standard for disease classification or diagnosis. Classification criteria have been developed in an attempt to define homogenous groups of SLE patients for clinical research. They have been mainly validated in adult cohorts, given the much lower prevalence of SLE before puberty. The three commonly used sets of current classification criteria and their validation studies to date are described in this review. Challenges relating to classification of SLE patients, including important differences across age-groups and ethnicities, are explored along with future directions in the classification of SLE.
•EULAR/ACR-2019 exhibit high sensitivity and specificity in adult-onset SLE.•Concerns about their performance in the paediatric age group may be linked to pathophysiology.•EULAR/ACR-2019 criteria allow the definition of homogenous study cohorts.•Classification criteria should not be used for diagnosis.
Abstract Chronic recurrent multifocal osteomyelitis (CRMO) is characterized by reduced activation of protein kinases ERK1 and 2 in monocytes resulting in impaired IL-10 expression. IL10 and its ...homologs IL19 and IL20 are organized in the IL10 cluster on chromosome 1q32. IL-10 and IL-19 are immune-regulatory cytokines, while IL-20 acts in a pro-inflammatory manner. The NLRP3 inflammasome, a multi-protein complex forming in response to innate stimuli, mediates IL-1β cleavage and release. Here, we investigated IL-10-related cytokine expression in CRMO monocytes, underlying molecular events, and effects on inflammatory responses. We observed reduced anti-inflammatory IL-10 and IL-19 expression, and enhanced IL-20 expression in CRMO monocytes. Reduced IL-10 and IL-19 expression was associated with impaired Sp-1 recruitment to regulatory regions, contributing to NLRP3 inflammasome activation, which may induce inflammatory bone-loss. Our findings underscore the importance of balanced receptor-, cell-, and tissue-specific cytokine expression for immune homeostasis, providing additional arguments for cytokine blocking strategies in CRMO.
Historically, osteomyelitis was considered an infectious disorder. More recently, inflammatory mechanisms were recognized causing a significant proportion of pediatric osteomyelitis. This study was ...to compare characteristics of children with chronic non-bacterial (CNO) and bacterial osteomyelitis (BOM). A chart review of osteomyelitis patients from the departments of pediatrics, pediatric surgery, orthopedic surgery, and oral and maxillofacial surgery was conducted in a tertiary referral center, covering the years 2004–2014. Institutional incidences of CNO (
n
= 49) and BOM (
n
= 56) were comparable. Differentiation between CNO and BOM based on clinical or laboratory findings was mostly impossible. However, children with BOM more frequently presented with local inflammatory signs (47 vs. 68 %,
p
= 0.040), fever (12 vs. 38 %,
p
= 0.003), and abscesses (0 vs. 39 %,
p
< 0.001). Peripheral arthritis (14 vs. 0 %,
p
< 0.001), inflammatory bowel disease (10 vs. 2 %,
p
= ns), and hyperostosis (29 vs. 4 %,
p
= 0.001) were more common in CNO. Whole-body MRI was performed in 76 % of CNO patients, unveiling multifocal lesions in 80 % (CRMO). Though considered a rare disorder, institutional incidences of CNO were comparable to BOM, and the discrimination between CNO and BOM solely based on clinical aspects was mostly impossible. This is of special interest, since a correct and timely diagnosis is of utmost importance for long-term outcomes in both disorders. Whole-body MRIs should be considered in chronic osteomyelitis to (1) detect clinically inapparent lesions in CNO and (2) indirectly exclude (usually unifocal) chronic bacterial infections. Prospective studies are warranted to establish evidence-based diagnostic and therapeutic approaches to CNO.
Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, ...corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue p = 0.003 and/or arthritis p = 0.002 were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex p = 0.027, more lesions on MRI p = 0.01 and higher CRP levels p = 0.03. Randomized clinical trials are needed to confirm observations and generate evidence.
•In the absence of clinical trials, treatment of CNO is empiric.•TNF inhibitors and pamidronate are effective in CNO.•Pamidronate induces remission more rapidly, TNF inhibitors are associated with fewer flares.•Failure to respond to pamidronate is associated with female sex, high numbers of bone lesions, and elevated CRP.•Observations argue for the use of TNF inhibitors and/or pamidronate in CNO.
Abstract Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, ...and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced ( p < 0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.
Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that predominantly affects children and young people. The pathophysiology and molecular mechanisms of CNO remain poorly ...understood, and diagnostic criteria and biomarkers are lacking. As a result, treatment is empiric and follows personal experience, case series and expert consensus plans.
A survey was designed to gain insight on clinician and patient experiences of diagnosing and treating CNO and to collate opinions on research priorities. A version containing 24 questions was circulated among international expert clinicians and clinical academics (27 contacted, 21 responses). An equivalent questionnaire containing 20 questions was shared to explore the experience and priorities of CNO patients and family members (93 responses).
Responses were used to select topics for four moderated roundtable discussions at the "International Conference on CNO and autoinflammatory bone disease" (Liverpool, United Kingdom, May 25-26
, 2022). The group identified deciphering the pathophysiology of CNO to be the highest priority, followed by clinical trials, necessary outcome measures and classification criteria. Surprisingly, mental wellbeing scored behind these items.
Agreement exists among clinicians, academics, patients and families that deciphering the pathophysiology of CNO is of highest priority to inform clinical trials that will allow for the approval of medications for the treatment of CNO by regulatory agencies.
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