ObjectivesTo test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease.MethodsThis cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling.ResultsThe majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients’ primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow.ConclusionROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.

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T he elderly constitute an ever-increasing proportion of the US population. There was a 15% increase in the number of people older than age 65 between 2000 and 2010, 1 more than initially predicted by the US Census. 2 The same model forecasts a more than 70% increase in the same cohort over the next 20 years, and a more than 60% increase in those older than age 85. Already health care cost per capita for those older than age 65 is estimated to be 3 to 5 times greater than for those younger than age 65.3 A shift from acute care to chronic disease management and long-term health care modalities is anticipated. Simultaneous to this increase in the elderly population is a marked expansion in medical technology. Testing and procedural intervention are becoming not only more numerous, but far more sophisticated and costly.As the proportion of the elderly population expands and medical technology advances, a rapidly increasing percentage of health care resources is being allocated to care at the end of life (EOL). However, it is unclear whether such resources provide value. In this context, there is a need to understand how such resources are utilized and how utilization decisions are made.Variation in the use of EOL resources and decisions is attributed to patient variables, hospital factors, and the sociocultural platform in which both patient and provider exist. [4][5][6] This article focuses on patient variables and employs a systematic approach to advance our understanding of factors that influence EOL care. In particular, we explore recent findings that minority patients are more likely to receive overtreatment and discuss possible explanations.