Rheumatology News

9 RHEUMATOID ARTHRITIS

Vol. 4 • No. 1 • 2016 • R heumatology N ews

Potential etanercept response biomarker identified

Greater myocardial inflammation found in RA patients after heart attack

BY NICOLA GARRETT Frontline Medical News From Arthritis & Rheumatology

BY NICOLA GARRETT Frontline Medical News From Arthritis Care & Research R ecording the temperature of skin over an inflammed joint may identify rheumatoid arthritis patients at high risk of joint damage, an exploratory study suggested. Dermal joint temperature could become a screening test to “quickly and accurately” identify individual RA patients at high risk for radiographic damage and those who may benefit from biologic therapy, said Dr Maria Greenwald, a rheumatolo- gist in group practice in Palm Desert, California, and her colleagues. During 2009–2014, the investigators enrolled seropositive RA patients who were on stable doses of methotrexate (20–25 mg/wk) for the past 3 months and did not use biologics or other disease-modifying antirheumatic drugs. It took 9 months to enrol 104 patients with cool joints and 42 months to enrol 104 patients with hot joints, suggesting “that at a single office visit, RA Selecting the right therapy the first time for patients with RA is a research priority because very good disease control is only achieved with etanercept in 30% of patients and other biologic therapies targeting other pathways besides tumour necrosis factor are available, wrote researchers led by Dr Darren Plant of the National Institute for Health ResearchManchester Musculoskeletal Biomedical Research Unit at the Manchester (England) Acad- emy of Health Sciences ( Arthritis Rheumatol 2016 Jan 27. doi: 10.1002/art.39590). Their study selected 72 patients from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) longitudinal cohort based on having an extreme response phenotype after 3 months of treatment with etanercept. DNA from each patient was sampled before therapy was initiated. A total of 36 patients were very good responders to etanercept and in clinical remission, defined by having a 28-joint Disease Activity Score (DAS28) of less than 2.6. The 36 patients classified as nonresponders to etanercept had a DAS28 improvement of less than 0.6 or an endpoint DAS28 of greater than 5.1. Following bisulfite conversion of the DNA, the research team used the HumanMethylation450 BeadChip to determine unmethylated versus methylated cytosines in the DNA and found five differentially methylated sites associated with response to etanercept that passed the 5% false discovery rate threshold. R esearchers have identified DNA methyla- tion as a potential biomarker of response to etanercept in an epigenome-wide association study of a longitudinal cohort of patients with rheumatoid arthritis. The results indicate that DNA methylation profiling may provide a new biomarker of response to etanercept in patients with RA.

BY JEFF EVANS Frontline Medical News

From the International Journal of Cardiology T he presence of rheumatoid ar- thritis in individuals who died from a myocardial infarction was associated with greater inflam- matory burden at different levels of myocardial tissue than in those without the disease in a small, retro- spective, case-control autopsy study. “These findings support the hy- pothesis that rheumatoid arthritis (RA) patients are prone to develop more vulnerable plaques due to more inflammation in the coronary arteries, but also develop increased intramyocardial inflammation indic- ative of a higher risk of myocardial tissue damage post MI. This might not only explain the higher inci- dence of cardiovascular events in this population, but also the higher fatality rate after myocardial infarc- tion,” wrote Dr Inge AM van den Oever of the Amsterdam Rheuma- tology and Immunology Center and colleagues ( Int J Cardiol 2016 Feb 3. doi: 10.1016/j.ijcard.2016.02.065). The investigators took tissue sam- ples from the infarcted left ventricle and microscopically determined in- farct border area of five patients with RA and MI and five controls with MI but without RA. They found that RA patients had a greater burden of inflammatory cells in the adventitia of infarct-related epicardial coronary arteries, the intramyocardial vascula- ture, and the border area of the in- farcted heart, compared with controls matched for age, sex, year of death, grade of stenosis, and infarct phase. Specifically, the adventitial layer of the infarct-related epicardial coronary artery of RA patients had significantly more lymphocytes and mast cells. Intramyocardial arteries in infarct and infarct border areas of RA patients, compared with con- trols, showed significantly greater staining for advanced glycation end product N-epsilon-(carboxymethyl) lysine (CML), which is thought to reflect oxidative damage to cells, as well as noninfarcted tissues taken from the right ventricle. The researchers included cases and controls from a postmortem tis- sue database of subjects who under- went autopsy within 24 hours after death at the VU University Medical Centre, Amsterdam, between Janu- ary 1990 and December  2010. The research was partly funded by a grant from the Dutch Society for Rheumatology. The authors had no conflicts of interest to declare.

“The results indicate that DNA methylation profiling may provide a new biomarker of response to etanercept in patients with RA,” concluded the researchers, who said that the study is the first to investigate the influence of epigenetic varia- tion on response to biologic therapies. Validation in a larger independent cohort is needed before transfer to clinical practice would be possible, they said.

The most compelling evidence for differential methylation was observed in the LRPAP1 gene located on chromosome 4. This gene encodes a chaperone of low density lipoprotein receptor- related protein 1 (LRP1), which is known to influence TGF-beta activity. Four CpG sites within exon 7 of the LRPAP1 gene were more methylated in nonresponders, results showed.

‘Hot’ joints may predict RA joint damage

patients on methotrexate are five times more likely to have cool joints than hot joints,” the researchers reported. The results showed that patients in the hot- joint cohort had a nearly fourfold higher risk of x-ray damage at 1-year follow-up, compared with those with cool joints (change in modified van der Heijde total Sharp score [mTSS]: 8.7 vs 2.5; P < 0.001). Patients with hot joints had an average joint temperature exceeding central forehead body temperature by 1.1° F, whereas those with cool joints had an average joint temperature of 4.3° F below central forehead body temperature. In the cohort of patients with hot joints, 74% had clear x-ray evidence of new joint damage (mTSS of 5 or greater), compared with 7% of cold-joint cohort patients at 1-year follow-up. Joint temperature at the hand or wrist predicted x-ray damage in the next year with 92% sensitivity and 78% specificity. ( Arthritis Care Res 2015 Dec 14. doi: 10.1002/acr.22813). Patients in the hot-joint cohort were younger,

Patients in the hot-joint cohort had a nearly fourfold higher risk of x-ray damage at 1-year follow-up, compared with those with cool joints.

had more recent onset of RA, and had a signifi- cantly higher Westergren erythrocyte sedimenta- tion rate than patients in the cool-joint cohort, the investigators noted. They suggested a future study might define a hot-joint cohort as RA patients with a joint that measures over a set point such as 36.6˚C. “Such a cutoff would make assessment very simple and would maintain the specificity and sensitivity of the model,” they said.

No conflicts of interest were disclosed.