LIVERPOOL, ENGLAND — People with rheumatoid arthritis (RA) have a consistently higher risk for venous thromboembolism (VTE) than the general population, but the reasons for this remain unclear, research presented at the British Society for Rheumatology (BSR) 2024 Annual Meeting reaffirmed.
Regardless of age, sex, body mass index (BMI), duration of disease, use of estrogen-based oral contraceptives, or hormone replacement therapy (HRT), people with RA are more likely to experience a pulmonary embolism or deep vein thrombosis than those without RA.
However, "these are rare events," James Galloway, MBChB, PhD, professor of rheumatology and deputy head of the Centre for Rheumatic Diseases at King's College London in England, said at the BSR 2024 Annual Meeting.
In one analysis of data from 117,050 individuals living in England and Wales that are held within a large primary care practice database, Galloway and colleagues found that the unadjusted incidence of VTE in people diagnosed with RA (n = 23,410) was 0.44% vs 0.26% for matched controls within the general population (n = 93,640).
RA and VTE Risk
The overall risk for VTE was 46% higher among people with RA than among those without, although the absolute difference was small, Galloway reported.
"RA is associated with an increased risk of VTE; that's been well described over the years," Galloway told Medscape Medical News. Past research into why there is an elevated risk for VTE in patients with RA has often focused on the role of disease activity and inflammation.
"In the last few years, a new class of drugs, the JAK [Janus kinase] inhibitors, have emerged in which we have seen a signal of increased VTE risk from a number of studies. And I think that puts a spotlight on our understanding of VTE risk," Galloway said.
He added "JAK inhibitors are very powerful at controlling inflammation, but if you take away inflammation, there is still an excess risk. What else could be driving that?"
To examine the excess risk for VTE seen in people with RA, Galloway and colleagues performed three separate analyses using data collected between January 1999 and December 2018 by the Royal College of General Practitioners Research and Surveillance Center.
One analysis looked at VTE risk according to age, sex, and BMI; another looked at the effect of the duration of RA; and a third analysis focused on the use of estrogen-based oral contraceptives or HRT.
For all three analyses, those with RA were matched in a 4:1 ratio to people from the general population without RA on the basis of current age, sex, calendar time, and years since registration at the primary care practice.
Observational Data Challenged
"These are observational data, so it's important to weigh up the strengths and limitations," Galloway acknowledged. Strengths are the large sample size and long follow-up provided by the database, which assesses and monitors more than 2000 primary care practices in England and Wales.
Confounding is still possible, despite adjusting for multiple factors that included sociodemographic factors; clinical features; and VTE risk factors such as smoking status, alcohol use, thrombophilia, reduced mobility, lower limb fracture, and a family history of VTE if data had been available. There wasn't information on disease activity, for example, and disease duration was used as a surrogate marker for this.
Sitting in the audience, Marwan Bukhari, MBBS, PhD, challenged the population-matching process.
"Do you think maybe it was the matching that was the problem?" asked Bukhari, who is consultant rheumatologist at University Hospitals of Morecambe Bay NHS Foundation Trust and an honorary senior lecturer at The University of Manchester, both in England.
"They're not entirely matched completely, correctly. Even if it is 4:1, there's a difference between the populations," he said.
Age, Sex, and Bodyweight
Over an average of 8.2 years' follow-up, the adjusted hazard ratios (aHRs) comparing VTE risk in women and men with and without RA were a respective 1.62 and 1.52. The corresponding aHRs for VTE according to different age groups were 2.13 for age 18-49 years, 1.57 for age 50-69 years, and 1.34 for age 70 years and older.
"The highest excess risk was in the youngest age group," Galloway pointed out, "but all age groups showing a significant increased risk of venous thromboembolism."
Similar findings were seen across different BMI categories, with the highest risk occurring in those in the lowest BMI group. The aHRs were 1.66, 1.60, and 1.41 for the BMI categories of less than 25 kg/m2, 25-30 kg/m2, and more than 30 kg/m2, respectively.
Duration of RA
As for disease duration, nearly two thirds (63.9%) of the 23,410 adults with RA included in this analysis were included at or within 2 years of a diagnosis of RA, 7.8% within 2-5 years of diagnosis, 9.8% within 5-10 years of diagnosis, and 18.5% at 10 or more years after diagnosis.
The aHR for an increased relative risk for VTE in people with RA vs the control group ranged from 1.49 for 0-2 years of diagnosis up to 1.63 for more than 10 years since diagnosis.
"We could see no evidence that the VTE excess risk in rheumatoid arthritis was with a specific time since diagnosis," Galloway said in the interview. "It appears that the risk is increased in people with established RA, whether you've had the disease for 2 years or 10 years."
Similar findings were also seen when they looked at aHRs for pulmonary embolism (1.46-2.02) and deep vein thrombosis (1.43-1.89) separately.
Oral Contraceptives and HRT
Data on the use of estrogen-based oral contraceptives or HRT were detailed in a virtual poster presentation. In this analysis, there were 16,664 women with and 65,448 without RA, and the average follow-up was 8.3 years.
"The number of people available for this analysis was small, and bigger studies are needed," Galloway said in the interview. Indeed, in the RA group, just 3.3% had used an estrogen-based oral contraceptive and 4.5% had used HRT compared with 3.9% and 3.8% in the control group, respectively.
The overall VTE risk was 52% higher in women with RA than in those without RA.
Risk for VTE was higher among women with RA regardless of the use of estrogen-based oral contraceptives or not (aHRs, 1.43 and 1.52, respectively) and regardless of the use of HRT or not (aHRs, 2.32 and 1.51).
Assess and Monitor
Together these data increase understanding of how age, gender, obesity, duration of disease, and estrogen-based contraception and HRT may make a difference to someone's VTE risk.
"In all people with RA, we observe an increased risk of venous thromboembolism, and that is both relevant in a contemporary era when we think about prescribing and the different risks of drugs we use for therapeutic strategies," Galloway said.
The overall take-home message, he said, is that VTE risk should be considered in everyone with RA and assessed and monitored accordingly. This includes those who may have traditionally been thought of as having a lower risk than others, such as men vs women, younger vs older individuals, and those who may have had RA for a few years.
The research was funded by Pfizer. Galloway reported receiving honoraria from Pfizer, AbbVie, Biovitrum, Bristol Myers Squibb, Celgene, Chugai, Galapagos, Janssen, Lilly, Novartis, Roche, Sanofi, Sobi, and UCB. Two coauthors of the work were employees of Pfizer. Bukhari had no conflicts of interest and was not involved in the research.