Combination Therapy of Abatacept and Anakinra in Children with Refractory Systemic Juvenile Idiopathic Arthritis: A Retrospective Case Series: Table 1.

Record, Jessica L.; Beukelman, Timothy; Cron, Randy Q.

doi:10.3899/jrheum.100726

Cited by 73 publications

(41 citation statements)

References 8 publications

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“…It has also been observed that children with sJIA have an increased proportion of the proinflammatory Th1 and Th17 cells, relative to age-matched healthy subjects (22). Additionally, two studies of abatacept (CTLA4-Ig), which prevents T-cell activation by inhibiting costimulation through CD80 and CD86, found it to be an effective treatment for children with chronic, articular sJIA (7) and recalcitrant sJIA with systemic features (8).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Ombrello¹,

Remmers²,

Tachmazidou³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

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Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10−17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10−5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10−16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11—HLA-DQA1*05—HLA-DQB1*03 haplotype [6.4 × 10−17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

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Section: Discussionmentioning

confidence: 99%

“…inflammatory features that tend to respond to anti-IL-1 therapies (6) and others following an arthritis-predominant disease course that may ultimately lead to chronic, destructive, treatment-refractory arthritis (7,8).…”

Section: Significancementioning

confidence: 99%

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Ombrello¹,

Remmers²,

Tachmazidou³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

View full text Add to dashboard Cite

show abstract

“…Similarly, treatment refractory adult Still disease (likely related or identical to sJIA but in adults) with MAS has been described as having miraculously responded to anakinra therapy by several groups. 119 --128 Although anakinra appears to be extremely safe, as a recombinant human protein with a short halflife (B3 hours), 129 and a large therapeutic window (1 --48 mg kg À1 per day), 118,130 there has been a report of hepatitis attributed to anakinra in children with sJIA. 131 Moreover, there has also been the suggestion that anakinra triggered MAS in two children with sJIA 132,133 but once again, cause and effect is difficult to establish.…”

Section: Il-1 Blockade For the Treatment Of Mas In Children With Sjiamentioning

confidence: 99%

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

et al. 2012

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Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30 --40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro-and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

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“…Abatacept has been shown to be beneficial in some cases of s-JIA; however, the majority of the subjects in this retrospective study had arthritis but not active systemic features (e.g., fever, rash). Because the mechanism of action (costimulatory molecule blockade) is different from that of the other biologic agents used to treat s-JIA (cytokine blockade), some investigators feel that abatacept may be safely used in combination with other biologics in patients with severe s-JIA (68). Further studies evaluating the efficacy of abatacept in certain clinical subgroups of s-JIA patients would be helpful.…”

Section: Other Therapeutic Strategiesmentioning

confidence: 99%

Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis

Correll

Binstadt

2013

Pediatr Res

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Combination Therapy of Abatacept and Anakinra in Children with Refractory Systemic Juvenile Idiopathic Arthritis: A Retrospective Case Series: Table 1.

Cited by 73 publications

References 8 publications

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis

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Combination Therapy of Abatacept and Anakinra in Children with Refractory Systemic Juvenile Idiopathic Arthritis: A Retrospective Case Series: Table 1.

Cited by 73 publications

References 8 publications

HLA-DRB1*11and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

HLA-DRB1*11and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis

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Product

Resources

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HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis