Annual European Congress of Rheumatology (EULAR) 2018, Amsterdam

<h3>Results of study suggest siblings of patients with rheumatoid arthritis are at increased risk of acute coronary syndrome</h3>

The results of a study presented at the Annual European Congress of Rheumatology (EULAR 2018) demonstrate an increased risk of acute coronary syndrome (ACS) in siblings of individuals with rheumatoid arthritis (RA), suggesting shared susceptibility between the two diseases.

Recent studies have demonstrated that severity of RA is associated with the risk of ACS, suggesting that it is the RA disease itself contributing to the excess risk.

A recently-published report demonstrated that despite more efficient control of inflammation in RA during recent years, the excess risk for ACS among patients with RA compared to the general population remains elevated. This suggests there may be a shared susceptibility between the two conditions.

To examine this, study authors investigated the risk of ACS in siblings of individuals with RA. If there were shared susceptibility between the two conditions, non-RA siblings would also have an increased risk of ACS due to their similar genetic set-up and background.

This Swedish Rheumatology Quality (SRQ) register is linked to the Swedish Multigeneration Register, Patient Register, the Cause of Death Register, and the Total Population Register. Through this, investigators identified 7,492 patients with RA from the SRQ (1996-2015) who had 10,671 full siblings; the patients with RA were matched for age and gender with 35,120 comparator subjects, along with their 47,137 full siblings.

Results showed that patients with early RA and their siblings were 44 per cent and 23 per cent more likely to suffer from an ACS event than matched comparator subjects from the general population. A direct comparison of patients with RA to their siblings demonstrated that those with RA had a 19 per cent higher risk of ACS than their siblings.

“Our results provide evidence of shared susceptibility between RA and ACS,” said study author Dr Helga Westerlind, Karolinska Institutet, Sweden. “Although the nature of this needs to be further investigated, we believe that to bring down the cardiovascular risk in patients with RA, cardio-preventive measures must go beyond optimised RA disease control.”

<h3>Gout in the elderly linked to higher risk of dementia</h3>

The results of a US study presented at EULAR 2018 suggest that gout is associated with a 17-to-20 per cent higher risk of dementia in the elderly.

The study included 1.23 million Medicare beneficiaries, of which 65,325 had incident dementia. In an analysis, which was adjusted for various potential confounding variables, including demographics, comorbidities and commonly-used medications (HR 1.17, 95 per cent CI 1.13-1.21), the results showed that gout is independently associated with a significantly higher risk of dementia. The association was larger in older age groups, females, African-American race and people with higher medical comorbidity.

Subgroup analyses indicated that gout was associated with a significant 20-to-57 per cent (p<0.0001) increase in dementia in patients without key comorbidities: Coronary artery disease (CAD); hyperlipidaemia; cardiovascular disease; diabetes; or hypertension. However, this was not the case in patients with each of these comorbidities, except in patients with CAD.

“Our study found a considerable increased risk of dementia associated with gout in the elderly,” said study author Dr Jasvinder Singh, Professor of Medicine and Epidemiology at the University of Alabama, Birmingham, US. “Further study is needed to explore these relationships and understand the pathogenic pathways involved in this increased risk.”

“We welcome these results, as they contribute to our understanding of the relationship between uric acid and dementia,” said Prof Robert Landewé, Chairperson of the Scientific Programme Committee, EULAR. “Previous studies have shown contradictory results, with some indicating an increased risk of dementia, while others reporting the opposite.”

<h3>Combining NSAIDs and TNF inhibitors may reduce radiographic progression in ankylosing spondylitis</h3>

The results of a cohort study presented at EULAR 2018 showed that, in patients with ankylosing spondylitis (AS) taking TNF inhibitors, the addition of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with significantly less radiographic progression in a dose-related manner at four years.

When looking at specific NSAIDs, celecoxib in combination with TNF inhibitor use was associated with the greatest reduction in radiographic progression, which was significant at both two and four years.

NSAIDs remain first-line therapy for patients with AS. If patients have a poor response, contraindications or intolerance to NSAIDs, they may then be given TNF inhibitors. Current treatment practice is based on symptomatic relief, however there is also some evidence that NSAIDs slow radiographic progression if taken continuously.

The evidence for the impact of TNF inhibitors on radiographic progression is unclear despite their good clinical efficacy. Many patients discontinue NSAIDs when they are put onto TNF inhibitors due to good symptom control; therefore there is very limited data on the impact of combined therapy on radiographic progression.

“Radiographic progression has an important bearing on patient mobility, as well as affecting their general wellbeing and day-to-day living,” said Prof Robert Landewé, Chairperson of the Scientific Programme Committee, EULAR. “We welcome these results that support a potential disease-modifying effect in patients with ankylosing spondylitis taking current therapies.”

This prospective cohort study included 519 patients with AS who met the modified New York criteria with at least four years of clinical and radiographic follow-up. The average age of participants was 41.4 years, with an average symptom duration of 16.8 years and three-quarters were male. NSAIDs were used in 66 per cent of patients (half using an index below 50 and half above). TNF inhibitors were used in 46 per cent of patients.

After baseline measures, clinical and medication data were collected every six months and radiographs performed every two years. Radiographic progression was measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Statistical analysis, which accounted for time-varying covariates, was used to estimate the causal effect of TNF inhibitors and NSAIDs on radiographic progression. The analysis was adjusted for gender, race/ethnicity, education, symptom duration, enrolment year, number of years on TNF inhibitors, symptom duration at time of TNF inhibitor start, baseline measurement scores (mSASSS, ASDAS-CRP), current smoking, and missed visit status.

In patients taking TNF inhibitors, the addition of NSAID therapy was associated with less radiographic progression in a dose-related manner at four years. Mean difference in mSASSS between TNF inhibitor use and no TNF inhibitor use at four years was 0.50 (p=0.38), -1.24 (p<0.001), and -3.31 (p<0.001) for no NSAID, low NSAID, and high NSAID use. The mean difference in mSASSS between TNF inhibitor and no TNF inhibitor use for celecoxib was -3.98 (p<0.001) and -4.69 (p<0.001) at two and four years, respectively.

“Our results suggest that the use of TNF inhibitors and NSAIDs, particularly celecoxib, have a synergistic effect to slow radiographic progression in AS patients, particularly at higher doses,” said study author Prof Lianne Gensler, Associate Professor of Medicine, University of California, San Francisco, US.

“This is the first study to compare whether effects are comparable among different NSAIDs in this setting.”

<h3>Positive clinical advances in systemic lupus erythematosus</h3>

The results of two studies presented at EULAR 2018 demonstrate exciting advances for individuals suffering from systemic lupus erythematosus (SLE).

The first is a phase 2 clinical study of a promising oral treatment, baricitinib. The second demonstrates the effective use of the shingles vaccine in SLE patients who are particularly prone to this infection.

“Novel therapeutic strategies are needed for SLE, which causes significant morbidity and mortality, and so we are delighted to see the positive results from the phase 2 trial of baricitinib,” said Prof Thomas Dörner, Chairperson of the Abstract Selection Committee, EULAR. “In addition, we welcome data on the vaccination of SLE patients against shingles, as currently, there is considerable clinical uncertainty around this issue.”

Treatment of SLE traditionally involves non-specific anti-inflammatory or immunosuppressive medications. However, this approach is ineffective in many patients and can be associated with many undesirable side-effects.

In the new phase 2 study, SLE patients taking baricitinib (an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 approved for the treatment of rheumatoid arthritis in Europe and Japan) had a significant improvement in several clinical outcomes compared to placebo.

This study included 314 patients with SLE receiving stable background therapy who were randomised 1:1:1 to placebo, baricitinib 2mg or 4mg once daily. Patients on baricitinib 4mg achieved significant resolution of arthritis or rash (Systemic Lupus Erythematosus Disease Activity Index 2000, SLEDAI-2K) compared with placebo (67 per cent vs 53 per cent, p<0.05), which was the primary end-point of the study. Patients on baricitinib 4mg also achieved a significantly greater SLE Responder Index (SRI-4) response (64 per cent vs 48 per cent, p<0.05), as well as flare reduction (SELENA-SLEDAI Flare Index), improvement in Lupus Low Disease Activity State (LLDAS) and reduced tender joint count. Rates of adverse events leading to treatment discontinuation and serious adverse events were higher for both baricitinib doses compared to placebo. There were no deaths, malignancies, major adverse cardiovascular events, tuberculosis, or serious herpes zoster infections; one case of deep-vein thrombosis was reported in a patient with risk factors.

“Our results demonstrated significant clinical improvements in SLE patients taking baricitinib versus placebo with an acceptable side-effect profile,” said Prof Daniel Wallace, Professor of Medicine, University of California and Associate Director, Rheumatology Fellowship Programme at Cedars-Sinai Medical Centre in California, US. “We look forward to progressing baricitinib in further clinical studies as a promising new treatment for people suffering with SLE.”

Meanwhile, a separate study showed that the live attenuated shingles vaccine was well tolerated and provoked an expected antibody response in stable SLE patients not receiving intensive immunosuppression.

Patients with SLE are 10 times more likely to contract shingles compared to healthy individuals and it can also affect them at an earlier age.

However, specific guidelines on the use of the shingles vaccine in SLE patients have been lacking, largely due to a theoretical concern of vaccine-induced infection, as well as a lack of clinical or experimental data upon which to base recommendations.

The study presented at EULAR 2018 included 90 patients with stable SLE who were not receiving intensive immunosuppression. All participants had a history of herpes zoster/chickenpox and were randomised to receive shingles vaccine or placebo. After six weeks, antibody levels in the vaccine group increased by 59.8 per cent versus a reduction of 2.1 per cent in the control group (p=0.01) demonstrating the effect of the vaccine. No serious adverse events were reported and none of the patients had clinical shingles infection post-vaccination.

“This is the first randomised, controlled trial to study the shingles vaccine in individuals with SLE. We hope our results will inform guidelines and ultimately lead to the safe administration of the vaccine in appropriate SLE patients to reduce the burden of shingles in these individuals,” said study author Dr CC Mok, Department of Medicine, Tuen Mun Hospital, Hong Kong.

<h3>Early, intensive treatment of RA provides long-term benefits and may normalise mortality rates — long-term follow-up study</h3>

The results of a 23-year, follow-up study presented at the European League Against Rheumatism (EULAR) Annual Congress 2018 suggest early, intensive treatment of rheumatoid arthritis (RA) has long-term benefits including the normalisation of mortality to levels consistent with the general population.

“We know that the adverse effects of rheumatoid arthritis on the body only become truly apparent after more than a decade,” said Prof Robert Landewé, Chairperson of the Scientific Programme Committee, EULAR. “Therefore, it is really interesting to see these data supporting early therapy after such a long period of follow-up.”

Mortality in patients with RA is higher than in the general population. There have been many advances in management which have demonstrated improved morbidity rates, however, evidence of improved mortality rates has remained elusive.

“Our results confirm that early, intensive treatment of rheumatoid arthritis, including use of glucocorticoids, has long-term benefits,” said Prof Maarten Boers, VU University Medical Centre, Amsterdam, The Netherlands (study author).

“Importantly, this study is one of the first to show a normalisation of RA mortality compared to the general population after 23 years of follow-up.”

This prospective study looked at the rate of mortality after 23 years follow-up of the COBRA (COmbinatietherapie Bij Reumatoide Artritis) trial.

In the original study, patients with early RA were treated with sulphasalazine (SSZ) monotherapy or a combination of SSZ, low-dose methotrexate and initially high, step-down prednisolone.

Results demonstrated the combined therapy regimen offered additional disease control over SSZ alone.

In 2010, after 11 years of follow up, another study showed numerically (but not significantly) lower mortality in patients on the combined therapy regimen compared to patients with SSZ monotherapy.

<h3>NSAIDs shown to have causal role in cardiovascular risk of patients with osteoarthritis</h3>

The results of a study presented at EULAR 2018 suggest that over two-thirds of the increased cardiovascular risk associated with osteoarthritis is linked to the use of non-steroidal anti-inflammatory drugs (NSAIDs), a mainstay of treatment for this condition.

Recent research suggests that osteoarthritis is an independent risk factor for cardiovascular disease (CVD) and several mechanisms have been suggested to account for this association. One of these is the frequent use of NSAIDs in the treatment of osteoarthritis as they have been shown to be a proven risk factor for CVD.

“The examination of cardiovascular risk among individuals with osteoarthritis is an important area of research as very little is known about the association, despite osteoarthritis being the most common rheumatic disease with high prevalence among the elderly,” said Prof Thomas Dörner, Chairperson of the Abstract Selection Committee, EULAR.

“This study is important because it provides new information about the potential causal role of NSAIDs for the observed cardiovascular complications among individuals with osteoarthritis.”

Results of the study demonstrate that people with osteoarthritis had a 23 per cent higher risk of developing CVD. The increased risk of congestive heart failure (CHF), ischaemic heart disease (IHD), and stroke was 42 per cent, 17 per cent and 14 per cent respectively. Investigators then calculated the impact of NSAID use on the increased risk and found that 68 per cent of the total effect of osteoarthritis on CVD risk was due to NSAID use. The proportion of the increased risk due to NSAIDs seen in CHF was calculated at 45 per cent and more than 90 per cent for IHD and stroke respectively.

This population-based cohort study used data from 7,743 osteoarthritis patients and 23,229 non-osteoarthritis controls matched for age and gender from health administrative data from British Columbia, Canada. Statistical analysis was used which adjusted the results for age, gender, socioeconomic status, body mass index, and several conditions known to be associated with CVD, such as chronic obstructive pulmonary disease (COPD), high blood pressure, diabetes, high cholesterol, and Romano comorbidity score.

“To the best of our knowledge, this is the first longitudinal study to evaluate the mediating role of NSAID use in the relationship between osteoarthritis and CVD in a large population-based sample,” said study author Prof Aslam Anis, School of Population and Public Health, University of British Columbia.

“Our results indicate that osteoarthritis is an independent risk factor for CVD and suggest a substantial proportion of the increased risk is due to the use of NSAIDs.

“This is highly relevant because NSAIDs are some of the most commonly used drugs to manage pain in patients with osteoarthritis.”