Rheumatoid Arthritis: Mortality Gap Narrows

Diana Swift

January 12, 2017

Compared with in the general population, 5-year excess mortality risk declined in patients with early rheumatoid arthritis (RA) and disease onset in 2000 or later, according to a Canadian study published online December 28 in the Annals of the Rheumatic Diseases.

The large population-based incident analysis found statistically significant relative risk reductions vs the general population in all-cause, cardiovascular, and cancer deaths, but not in deaths resulting from infection.

"In our cohort, during the first 5 years after RA diagnosis, the mortality gap between RA and the general population observed in people with RA onset on or before 2000 was not observed for people with RA onset after 2000," write Diane Lacaille, MD, a rheumatologist at the University of British Columbia in Vancouver, Canada, and colleagues.

"There's definitely been an improvement in mortality over the first 5 years of the disease," Dr Lacaille told Medscape Medical News. And although the study was not designed to evaluate the reasons for improvement, Dr Lacaille speculates that the improvement is a result of "a paradigm shift over those years in the way we treat RA."

More recent intensive treat-to-target regimens identify patients earlier and manage them more aggressively. "We target remission. Our target of treatment is to completely eradicate inflammation, which was felt to be responsible for the increased risk of mortality," Dr Lacaille said.

In addition, newer, more effective disease-modifying antirheumatic drugs (DMARDs), especially biologics, are used earlier and more intensively. "We've had these drugs for some, but before, if a patient was comfortable, we just left it, whereas now our goal is the absence of inflammation," she said.

Better survival could also be related to the natural evolution of the disease over time, according to the authors.

However, although the mortality rate in early RA appears to have drawn close to that of the general population, Dr Lacaille and associates warned that only longer follow-up will determine whether mortality differences between the two populations have been erased.

"[O]ne should be cautious about interpreting our results as indicating that mortality differences between RA and the general population no longer exist, as 5 years of follow-up is relatively short, and it is possible that differences between RA and the general population would be observed with longer follow-up, especially since previous studies have suggested that the greatest increase in mortality risk may occur after 7–10 years of disease."

The authors note, however, that in sensitivity analyses, Kaplan-Meier survival curves based on all available follow-up, as much as 8 years in the 2001 to 2006 cohort, yielded comparable results.

Improvements in Multiple Measures

For the current study, Dr Lacaille and colleagues analyzed physician billing data in British Columbia's provincial healthcare system database, comparing data from 24,914 incident cases of RA with an equal number of adults from the general population, matched for sex, birth year, and index year. The mean age in both groups was about 58 years, and about 66% were female.

Patients were diagnosed between January 1996 and December 2006, and followed to 2010. The researchers divided patients into early and late cohorts according to date of diagnosis: 1996 to 2000 vs 2001 to 2006.

Across the whole cohort, the researchers identified 2747 and 2332 deaths in case and control groups, respectively, and unadjusted mortality rates of 24.43 and 20.72 per 1000 person-years, respectively. The all-cause mortality rate ratio was 1.18 (95% confidence interval [CI], 1.12 - 1.25). Compared with control patients, patients with RA had more deaths per 1000 person-years from cardiovascular disease (8.49 vs 7.04) and from infections (1.45 vs 0.91). Deaths from cancer were virtually the same, at 6.48 and 6.20.

When analyzed by period, risk differed across incident cohorts for all-cause, cardiovascular, and cancer mortality (interactions P <.01). In the earlier period, patients with RA had a 40% higher relative risk for all-cause mortality compared with adults without RA (adjusted hazard ratio [aHR], 1.40; 95% CI, 1.30 - 1.51), but the difference was not apparent in the group diagnosed in 2000 or beyond (aHR, 0.97; 95% CI, 0.89 - 1.05).

Similarly, patients in the early cohort had a 45% excess risk for cardiovascular-related death compared with the general population (aHR, 1.45; 95% CI, 1.28 - 1.65), but no excess risk was seen in the late cohort (aHR, 0.94; 95% CI, 0.81 - 1.08).

For cancer-related death, patients in the early group had a 22% excess risk (aHR, 1.22; 95% CI, 1.06 - 1.41), but not those in the late cohort (aHR, 0.88; 95% CI, 0.75 - 1.02).

The investigators also saw a decline in infection-related deaths, but the confidence intervals were wider for both periods (early cohort: aHR, 1.94 [95% CI, 1.37 - 2.75]; late cohort: aHR, 1.27 [95% CI, 0.90 - 1.81]).

The authors point to the study's implications for patients, physicians, and policy makers. "It provides reassuring evidence suggesting that time trends in the disease itself and/or its management are having a beneficial impact on an outcome of utmost importance to people living with arthritis," they write.

Neil Ruderman, MD, a professor of medicine in the Division of Rheumatology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, agreed. "My take on the study is, it's more evidence that we're doing the right thing with targeted treatment," he told Medscape Medical News. Dr Ruderman was not involved in the study.

He noted that there is already compelling evidence showing that early intensive anti-inflammatory treatment reduces short-term cardiovascular and other morbidities and decreases the need for joint surgery. "This would be the icing on the cake if it also reduces mortality over time."

That would be highly consequential from a public health perspective, he added. "Death is an important endpoint, and preventing it is an important justification of the cost of therapy."

The authors called for further study of potential determinants and longer case-control comparisons based on more than 10 years' follow-up.

In Dr Ruderman's view, the mortality reduction is likely to endure over the longer term. "It was persistent in the study's sensitivity analyses at 8 years' follow-up, so it's likely not a short-term gain. Unless something changes dramatically over the next 10 years, I imagine it will hold up."

Mixed Results

However, other recent mortality analyses in patients with RA have shown mixed results. For example, a smaller study that included 2519 patients in the United Kingdom's Norfolk Registry reported that relative risk for death for patients with early RA, compared with the general population, had not significantly improved since 1990. Although crude mortality rates decreased slightly over time, they remained stable in comparison with declines in those of the general population. The researchers followed three time cohorts from 1990 to 2004, for a slightly longer period of 7 years.

In contradiction, however, a 2015 study that included more than 20,000 patients in the UK Health Improvement Network showed that in the last decade, increases in survival among patients with RA has actually outpaced that of the general population.

Similar to Dr Lacaille and Dr Ruderman, these researchers ascribed the improved survival to better treatment: more effective use of conventional and biologic DMARDs, as well as appropriate dosing and administration, new combination therapies, and early cardiovascular disease prevention.

"Although causality could not be determined from administrative data, rheumatologists like to think the decrease in mortality is due to more aggressive treatment and to less cardiovascular disease, which is the main cause of death in RA patients." Dr Ruderman said.

This study was funded by the Canadian Institute for Health Research. The authors and commentator have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online December 28, 2016. Abstract

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