Moving from nature to nurture: a systematic review and meta-analysis of environmental factors associated with juvenile idiopathic arthritis.

OBJECTIVES: JIA is the most common paediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanism and ultimately benefit patients. This review aimed to collate and synthesize the current evidence of environmental factors associated with JIA. METHODS: Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to January 2020. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesized in narrative form. RESULTS: This review includes 66 environmental factors from 39 studies (11 cohort and 28 case-control studies) over 45 years. Study sample sizes ranged from 41 to 1.9 million participants. Eight environmental factors from ten studies were meta-analysed. Caesarean section delivery was associated with increased JIA risk [pooled odds ratio (OR) 1.11, 95% CI: 1.01, 1.22]. Conversely, presence (vs absence) of siblings (pooled OR 0.60, 95% CI: 0.44, 0.81) and maternal prenatal smoking (pooled OR 0.70, 95% CI: 0.58, 0.84) were associated with decreased JIA risk. CONCLUSION: This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research undertaken over five decades. We also highlight the challenges of combining data collected over this period due to limited between study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies.

Assessing the Role of DNA Methylation-Derived Neutrophil-to-Lymphocyte Ratio in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a disease of chronic systemic inflammation (SI). In the present study, we used four datasets to explore whether methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) might be a marker of SI in new onset, untreated, and treated prevalent RA cases and/or a marker of treatment response to the tumour necrosis factor inhibitor (TNFi) etanercept. mdNLR was associated with increased odds of being a new onset RA case (OR = 2.32, 95% CI = 1.95-2.80, P < 2 × 10-16) and performed better in distinguishing new onset RA cases from controls compared to covariates: age, gender, and smoking status. In untreated preclinical RA cases and controls, mdNLR at baseline was associated with diagnosis of RA in later life after adjusting for batch (OR = 4.30, 95% CI = 1.52-21.71, P = 0.029) although no association was observed before batch correction. When prevalent RA cases were treated, there was no association with mdNLR in samples before and after batch correction (OR = 0.34, 95% CI = 0.05-1.82, P = 0.23), and mdNLR was not associated with treatment response to etanercept (OR = 1.10, 95% CI = 0.75-1.68, P = 0.64). Our results indicate that SI measured by DNA methylation data is indicative of the recent onset of RA. Although preclinical RA was associated with mdNLR, there was no difference in the mean mdNLR between preclinical RA cases and controls. mdNLR was not associated with RA case status if treatment for RA has commenced, and it is not associated with treatment response. In the future, mdNLR estimates may be used as a valuable research tool to reliably estimate SI in the absence of freshly collected blood samples.

Juvenile idiopathic arthritis-associated uveitis.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood, with JIA-associated uveitis its most common extra-articular manifestation. JIA-associated uveitis is a potentially sight-threatening condition and thus carries a considerable risk of morbidity. The aetiology of the condition is autoimmune in nature with the predominant involvement of CD4(+) T cells. However, the underlying pathogenic mechanisms remain unclear, particularly regarding interplay between genetic and environmental factors. JIA-associated uveitis comes in several forms, but the most common presentation is of the chronic anterior uveitis type. This condition is usually asymptomatic and thus screening for JIA-associated uveitis in at-risk patients is paramount. Early detection and treatment aims to stop inflammation and prevent the development of complications leading to visual loss, which can occur due to both active disease and burden of disease treatment. Visually disabling complications of JIA-associated uveitis include cataracts, glaucoma, band keratopathy and macular oedema. There is a growing body of evidence for the early introduction of systemic immunosuppressive therapies in order to reduce topical and systemic glucocorticoid use. This includes more traditional treatments, such as methotrexate, as well as newer biological therapies. This review highlights the epidemiology of JIA-associated uveitis, the underlying pathogenesis and how affected patients may present. The current guidelines and criteria for screening, diagnosis and monitoring are discussed along with approaches to management.

Macrophage Activation Syndrome.

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic diseases such as systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus. It is often considered a type of secondary hemophagocytic lymphohistiocytosis (HLH) and results from over-activation of T lymphocytes and macrophages leading to a "cytokine storm". Characteristic features are persistent fever, lymphadenopathy, hepatosplenomegaly, cytopenias (anemia, leucopenia, thrombocytopenia), raised C-reactive protein, falling erythrocyte sedimentation rate, hypofibrinogenemia, transaminitis, hypertriglyceridemia and extreme hyperferritinemia often associated with multi-organ impairment. Key to its management is early recognition of MAS which may be difficult due to similarity to systemic sepsis or flares of the underlying rheumatic disease. To aid with this process, criteria for the diagnosis of MAS in patients with sJIA derived by international consensus have been published. Although bone marrow biopsy showing hemophagocytosis is strongly supportive it is not essential for diagnosis. Together with appropriate supportive care, first-line treatment is high-dose intravenous corticosteroids with cyclosporin or intravenous immunoglobulin (IVIg) added if there is not initial response. Although etoposide is used by hematologists in treatment of HLH, there are concerns regarding organ toxicity and bone marrow suppression which weigh against its use in initial management of MAS. With increasing understanding of the pathogenesis of MAS, use of drugs targeting specific cytokines has been reported in case series. The relatively rapid effectiveness of anakinra, a recombinant IL-1 receptor antagonist, has been documented. Further studies of this and other biologic agents are required to identify the most effective and safest treatment option for refractory MAS.