Pharmacotherapeutic Considerations for Individuals with Down Syndrome

Hefti, Erik; Blanco, Javier G.

doi:10.1002/phar.1880

Cited by 19 publications

(15 citation statements)

References 55 publications

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“…We found an outsized risk of LD in children with T21 and sJIA. T21 carries increased susceptibility to adverse drug reactions62 and to viral pneumonia 63. Another contributing factor may be underlying type 1 interferonopathy, recently described in T21 64.…”

Section: Discussionmentioning

confidence: 99%

Emergent high fatality lung disease in systemic juvenile arthritis

et al. 2019

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ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

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Section: Discussionmentioning

confidence: 99%

Emergent high fatality lung disease in systemic juvenile arthritis

et al. 2019

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“…We found an outsized risk of LD in children with T21 and sJIA. T21 carries increased susceptibility to adverse drug reactions [61] and to viral pneumonia. [62] Another contributing factor may be underlying type 1 interferonopathy, recently described in T21.…”

Section: Discussionmentioning

confidence: 99%

An emergent, high-fatality lung disease in systemic juvenile arthritis

Saper

Chen

Deutsch

et al. 2019

Preprint

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Objective To investigate characteristics and risk factors of a novel parenchymal lung disease, increasingly detected in systemic juvenile idiopathic arthritis (sJIA). Methods In a multi-center retrospective study, 61 cases were investigated, using physician-reported clinical information and centralized analyses of radiologic, pathologic and genetic data. Results Lung disease (LD) was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the IL-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes +/- ground glass opacities. Predominant pathology (23/36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features, including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. 5-year survival was 42%. Whole-exome sequencing (20/61) did not identify a novel monogenic defect PAP-related or macrophage activation syndrome (MAS)-related mutations as likely primary cause. Trisomy 21 (T21) increased LD risk, as did young sJIA onset. Refractory sJIA was not required for LD development. Exposure to interleukin (IL)-1 and IL-6 inhibitors (46/61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but it was not associated with LD features. Conclusions A rare, life-threatening LD in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

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“…Furthermore, the intellectual disability associated with DS, as well as inadequacies in living arrangements, may be predisposing factors for poor medication adherence. 100 At this time, the treatments available for adults with DS and dementia are mainly supportive. Rivastigmine, galantamine, memantine, and donepezil have been used to treat DS-associated dementia.…”

Section: Managementmentioning

confidence: 99%