Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. METHODS: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. FINDINGS: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. INTERPRETATION: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems. FUNDING: The Instituto de Salud Carlos III.

The prevalence, correlates and treatment of pain in Spain.

OBJECTIVES: The aims of this paper are to report on the prevalence, correlates and treatment of pain in the adult Spanish population. The analysis also explores the association between the experience of pain and health-related quality of life (HRQoL), employment and productivity, and healthcare resource utilization. METHODS: Data are from the Internet-based, 2010 National Health and Wellness Survey (NHWS) Spain. The sample was weighted by age and sex to correspond to the 2010 adult Spanish population. All respondents to the NHWS reported on socio-demographic and economic characteristics, medication adherence and major health conditions. They also reported on their HRQoL (the SF-12), their employment status and workplace productivity experience (WPAI instrument) and their healthcare resource utilization. Persons reporting experiencing pain gave details on conditions causing pain, prescription and over the counter (OTC) medication utilization, duration of utilization and satisfaction with medications. A supplementary analysis evaluated the population prevalence of pain for the five most populous Spanish autonomous communities (regions). RESULTS: An estimated 6.10 million (17.25%) of the adult population of Spain reported experiencing pain in the last month. Of these 11.69% experienced severe pain, 64.17% moderate pain and 24.14% mild pain. Daily pain was experienced by 6.95% of the population The major conditions causing pain are back pain (60.53%) followed by joint pain (40.21%). Sleep difficulties (42.24%) and anxiety (40.62%) were most commonly cited as comorbidities. Prescription medication utilization was most important in the severe and moderate pain categories, with 71.62% reporting they were satisfied with their prescription pain medications. Adherence to pain medications was high with an overall Morisky score of 0.99 (range 0-4). Pain had a major negative effect on labor force participation for those reporting moderate and severe pain with a participation rate of only 42.62% for those with severe pain. Pain was associated with substantial health-related quality of life deficits as measured by the physical and mental score components of the SF-12. In the case of SF-6D utilities, the utility score for the pain population was markedly below that for the no-pain population (0.65 vs. 0.75; p < 0.05).The experience of pain also negatively impacted rates of absenteeism and presenteeism, as well as being associated with greater healthcare resource utilization. Finally, for the five most populous autonomous communities of Spain estimated pain prevalence ranged from 14.80% for Madrid to 18.79% for Comunidad Valenciana. The are a number of limitations which should be noted. First, this is an internet-based sample study and the respondent population may not be representative of the Spanish adult population. Second, respondents are asked to report their experience of pain with no independent clinical conformation. Finally, while a number of obvious acute pain categories are excluded, there is no attempt to arbitrarily define a chronic pain population or to identify pain categories such as neuropathic pain. CONCLUSIONS: The experience of pain represents a substantial burden on both individuals and the Spanish economy. The experience of pain is associated with a substantial reduction in both the PCS component of the SF-12 and SF-6D absolute utilities--most notably in respect of severe pain. The experience of pain is also associated, not only with reduced labor force participation and increased absenteeism and presenteeism, but with substantially higher patterns of healthcare resource utilization.