Passive smoking and air pollution – links to arthritis development and poor response to therapy

On the first day of the EULAR congress, speakers presented two studies which link passive smoking and air pollution to the development of rheumatoid arthritis (RA).

Smoking and RA

The first was a large population-based study of French women, which reports passive exposure to smoking during childhood or adulthood increases the risk of developing RA. Active smoking is known to increase your risk of developing RA, but little was known about whether passive smoking had an impact.

Nguyen and colleagues set out to investigate the relationship between passive smoking and RA by studying a large prospective cohort of health French women. They analysed data from the E3N-EPIC (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l’Education Nationale) which has collected data on French women since 1990.

They considered women to be exposed to passive smoking during childhood if they self-declared staying in a smoky room for several hours a day during childhood. For adults, those who were exposed for at least 1 hour a day were considered to be subject to passive smoking.

Out of the 79,806 women included in the study, 698 cases of RA were identified. In total, 10,810 women were exposed to passive smoking as children, while 42,036 were exposed to passive smoking as adults. Some 6,581 (8.25%) women were exposed to both, and 47,036 (58.9%) were exposed to either.

Across the cohort, passive smoking in childhood was positively associated with the risk of RA. However, when the researchers looked at the participant’s individual smoking habits, they found the association with increased RA risk was only among never-smoking women, not those who had ever themselves been a smoker.

These results suggest that actively or passively smoking by-products could generate autoimmunity, at least towards antigens involved in RA pathogenesis.

Air pollution and RA

The presentation also discussed the link between the lungs and inflammatory arthritis. In another study, Adami and colleagues considered a group of people living in the Verona area of Italy. The researchers looked at the association between concentration of air pollutants and biologic drug retention rates in people with chronic inflammatory arthritis (CIA).

The study compared the exposure to pollutants in 30-day and 60-day periods prior to a drug switch or swap due to disease progression.

In total, 1,286 patients with CIA were included, and 13,636 daily air pollution records were retrieved. The researchers found an exposure-dependent relationship between exposure to air pollutants and markers of inflammation in people with CIA.

Exposures greater than 50 μg/m3 had a 150% higher risk of having C-reactive protein (CRP) levels above 5 mg/L. Exposure levels of greater than 40 μg/m3 saw the risk decrease to 65%.

If the pollution threshold was set at 30 μg/m3 (below the European Union health protection limit) there was still a 38% higher risk of having altered CRP.

From these results, the authors concluded that environmental air pollution was a determinant of poor response to biologic treatment. They suggest interventions to decrease emissions from fossil fuels could have beneficial effects on the persistence rate of biologic treatments in people with inflammatory arthritis.


Covid-19 morbidity and mortality in people with rheumatic diseases: new data and insights from Spain and Sweden

Since the pandemic began, there have been concerns that those with inflammatory diseases may be at a higher risk of poor outcomes from Covid-19. However, currently the outcomes are not very well understood.

At the meeting, one presentation discussed a Spanish research paper, which the authors believe to be the largest study of its kind. The authors of the study (Arani Vivekanantham and colleagues) looked at whether individuals with rheumatoid arthritis (RA) had an increased risk of Covid-19 diagnosis, hospitalisation and death compared to the general population.

The study used population-based data from a database which covers over 80% of the population in Catalonia. The information was then linked to region-wide Covid-19 testing, hospital and mortality records. Outpatient diagnoses of Covid-19, hospitalisations and death were identified between 1st March and 6th May 2020.

Out of the 5,586,565 people identified, 16,344 had RA. Having RA was positively associated with being diagnosed and hospitalised with Covid-19. However, the authors did not find an association between RA and the risk of worsening from outpatient diagnosis to hospitalisation or death, or from hospitalisation to death.

Although this data shows a clear relationship, further research is needed to address factors linking RA and Covid-19 outcomes, including the presence of other comorbidities, underlying RA disease activity, and the use of immunosuppressive medications.

Another study, undertaken in Sweden, looked at all-cause mortality, absolute and relative risks for severe Covid-19 in people with chronic inflammatory joint diseases, compared both over time and to the general population.

Bower and colleagues used data from ARTIS, a Swedish national database, to look at hospitalisations, admission to intensive care, and deaths due to Covid-19. They analysed data from 110,567 people with inflammatory joint disease, including RA, psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, or juvenile idiopathic arthritis. These were compared to outcomes for 484,277 people in the general population.

The results showed that in all groups, the absolute risk of death from any cause in 2020 was higher than 2015–2019, but the relative risks of death versus the general population remained similar. In 2020, the risk of hospitalisation, admission to intensive care, and death due to Covid-19 for people with inflammatory joint disease was 0.5%, 0.04% and 0.1%, respectively.


Elderly patients are not at increased risk of serious infections with new disease-modifying antirheumatic drugs compared to conventional synthetic treatments

A new study has found that treatment with new classes of drugs, which are biologic disease-modifying anti-rheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi), is not associated with an increased risk of serious infection in elderly patients above 70 years of age.

This new evidence conflicts with findings of previous studies, which have found that elderly people with rheumatoid arthritis (RA) are generally at increased risk of serious infections and some anti-rheumatic treatments have been associated with a higher serious infection risk.

Strangfeld and colleagues analysed data from RABBIT, the German register for the long-term observation of therapy with biologics in adult patients with RA. Patients are enrolled when they start a new DMARD after failing at least one conventional synthetic treatment (csDMARD).

Their analysis included 2,274 people over the age of 70. In total, 626 serious infections were observed in 425 people.

The researchers found that serious infections were less likely in patients receiving bDMARDs or JAKi compared to csDMARDs, but this was not statistically significant.

Associations with an increased risk of serious infections were seen for glucocorticoid use, higher disease activity, and having another underlying disease such as chronic pulmonary or kidney disease, or diabetes. The authors also found that better physical capacity was associated with a decreased risk of having a serious infection.

Overall, the results suggest that treatment with these new classes of drugs is not associated with an increased risk of serious infection in RA patients above 70 years of age.


Decline in excess risk of dementia and heart failure in patients with rheumatoid arthritis

New data, presented at the congress, shows a substantial decline in the risk of both dementia and heart failure in people with rheumatoid arthritis (RA) onset in the 2000s as compared to 1980s – coinciding with the advent of novel biologic treatments for RA.

Heart failure is one of the most common cardiovascular conditions in people with RA, and previous studies have suggested that people with RA are twice as likely to develop heart failure as people in the general population without RA.

However, previous studies have delivered mixed results about the pattern of cognitive impairment and dementia in people with RA compared to the general population. It is also important to note that existing studies have not evaluated trends in incidence of dementia or heart failure to see if the risks have changed over time.

Now, two groups at the Mayo Clinic have run population-based studies in Minnesota to assess the incidence of dementia or heart failure over time in people with RA.

Vanessa Kronzer and colleagues assessed the incidence of dementia over time in people with RA and compared it to that seen in the general population. They collected medical record data and found 895 people diagnosed with RA between 1980 and 2009. All individuals were followed up routinely to see if any went on to develop dementia.

The 10-year cumulative incidence of dementia in people diagnosed during the 1980s, 1990s, and 2000s was 12.7%, 7.2%, and 6.2%, respectively – showing a clear decline and markedly lower cumulative incidence of dementia for people diagnosed with RA in the 2000s compared with the 1980s.

For 880 people in the general population without RA, the 10-year cumulative incidence of dementia in the 1980s, 1990s, and 2000s was 9.3%, 5.0%, and 7.1%, respectively. Overall, the risk of dementia in RA patients was significantly higher than in people without RA. When subdivided by decade, the risk of dementia in people diagnosed with RA was higher than non-RA comparators in the 1980s and 1990s – but not the 2000s.

Elena Myasoedova and colleagues assessed the incidence of heart failure in people with RA using the same methods. They looked at the data from 905 people diagnosed with RA and heart failure between 1980 and 2009.

The 10-year cumulative incidence of heart failure in people diagnosed with RA in the 1980s, 1990s, and 2000s was 8.5%, 10.8%, and 7.1%, respectively. These results show there was no difference in incidence of heart failure in the 1990s and 2000s compared to the 1980s.

For 903 people in the general population without RA over the same time period the incidence of heart failure was 7.4%, 7.5%, and 7.3%. When comparing the risk of heart failure in people with and without RA, those diagnosed with RA in the 2000s had no excess risk of heart failure compared to the general population. This finding is in contrast to the 2-fold excess risk seen in people diagnosed with RA in the 1980s, and around 1.5-fold increased risk in 1990s.

The researchers suggest further studies should investigate this association, looking at the role of inflammation, autoimmunity, and anti-rheumatic treatments in the risk of dementia and heart failure.


New long-term efficacy and safety analyses evaluating upadacitinib in patients with rheumatoid arthritis

At the congress, Abbvie announced new analyses showing patients with moderate to severe rheumatoid arthritis on background methotrexate (MTX) treated with 15 mg upadacitinib (Rinvoq) once daily maintained higher rates of clinical remission and low disease activity through three years compared to those patients treated with adalimumab (Humira). 

Additionally, a separate integrated safety analysis found the safety profile of upadacitinib was consistent over 4.5 years, with no new safety risks observed.

This analysis included data pooled from six rheumatoid arthritis Phase 3 clinical trials and included more than 3,000 patients with over 7,000 patient years of exposure of upadacitinib 15 mg, as well as data of adalimumab and MTX. 

In this integrated safety analysis, results showed that the safety profiles of upadacitinib 15 mg and adalimumab were generally similar, with the exception of higher rates of herpes zoster and blood CPK increase seen with upadacitinib 15 mg.

Most herpes zoster cases were non-serious (94 percent) and CPK elevations were mostly asymptomatic. The most common adverse events seen with upadacitinib 15 mg were upper respiratory tract infection, nasopharyngitis and urinary tract infection.

Rates of serious infections, malignancy (excluding non-melanoma skin cancer), MACE and VTE were broadly similar across upadacitinib and comparator-treatment groups. 

The rate of deaths in upadacitinib-treated patients with rheumatoid arthritis remains consistent with the background rate for patients with rheumatoid arthritis.

Belinda Byrne, Medical Director, AbbVie UK said: "We are dedicated to helping more people living with rheumatoid arthritis reach their care goals aimed at remission or low disease activity.

“These data reinforce the long-term efficacy and safety profile of upadacitinib in rheumatoid arthritis. We continue to advance research to provide valuable insights into the role that upadacitinib has in helping patients with rheumatoid arthritis.”