For rheumatoid treatment, the more medicine you take, the better the effect?

*Only for medical professionals to read for reference.
There is no end to learning, keep learning! Rheumatoid arthritis (RA) is an autoimmune disease with erosive arthritis as the main clinical manifestation, which can occur at any age
.

The pathogenesis of RA is currently unclear.
The basic pathological manifestations are synovitis, pannus formation, and gradual destruction of articular cartilage and bone, which eventually leads to joint deformities and loss of function, which can be complicated by cardiovascular diseases, tumors, depression, and infections.
, osteoporosis
.

At the 2021 European Union Against Rheumatism Online Annual Conference (EULAR 2021), chaired by the chairmen of the conference, Tsutomu Takeuchi and Claire Daien, a number of scholars were invited to conduct multi-faceted academic discussions on RA and its comorbidities
.

One.
The poor effect of multi-drug therapy on early RA The first academic report was presented by Dr.
Soraya of the French National Center for Scientific Research.
Her research team used data from the French cohort ESPOIR, which included 813 patients with early-onset RA
.

Patients enrolled in the current study must receive their first disease-improving anti-rheumatic drug (DMARD) within 24 months of being enrolled in the cohort
.

The response to treatment was assessed by achieving DAS28 ESR remission (REM) 1 year, 5 years, and 10 years after the onset of the first DMARD
.

The occurrence of serious adverse events (SAE) is measured by serious infections, hospitalizations, or deaths during the 10-year follow-up period
.

The correlation between patient characteristics and REM realization and SAE occurrence was tested in univariate analysis
.

Logistic regression model was used to evaluate the association between multi-drug therapy and REM at 1, 5, and 10 years
.

After multivariate adjustment of age, gender, BMI, disease duration, initial DAS28 ESR, initial HAQ, smoking status, and rheumatoid comorbidity index (RDCI), the conclusions of the study are as follows: 5 years after the first DMARD, The proportion of REM patients in the ≥2 drug treatment group was 45.
0%, while the 0-1 drug treatment group was 56.
3% (p=0.
03); at 10 years, the proportion of REM patients in the ≥2 drug treatment group was 36.
3%.
The rate in the 0-1 drug treatment group was 63.
7% (p=0.
006)
.

Patients taking ≥2 drugs are 40% less likely to achieve REM 5 years after the first DMARD (if RDCI is not included in the model) (OR=0.
60; 95%CI 0.
38-0.
94, p=0.
03); 10 At 1 year, the probability of achieving REM or low disease activity was reduced by 56% (OR=0.
44; 95%CI 0.
26-0.
77, p=0.
004)
.

The incidence of SAE is 61 cases per 1,000 patient-years
.

For patients with all causes of SAE, the multi-drug treatment group accounted for 71.
4%, while the non-multidrug treatment group accounted for 57.
8% (p=0.
03; univariate analysis)
.

The above results are no longer significant after adjusting the comorbidity index
.

Dr.
Soraya concluded that in this early RA cohort, multi-drug therapy is associated with poor response to treatment and increased risk of adverse events.
More research is needed to support multi-drug therapy as a tool for measuring comorbidities
.

two.
Increased mortality in RA patients with interstitial lung disease The second academic report was lectured by Dr.
Pierre from the University of Paris, France.
Dr.
Pierre and his collaborators used French administrative medical care from January 1, 2013 to December 31, 2018 A historical cohort study was conducted using data from the Health Care Database (SNDS) to assess the prevalence and incidence of clinical RA-ILD in France, and compare the mortality of RA-ILD patients and RA patients without clinical ILD (RA-noILD)
.

Cox proportional hazards regression was used to compare the mortality of RA patients with and without clinical ILD in a matched population
.

Figure 1 Mortality changes during follow-up Figure 2 Comparison of mortality between RA-ILD and RA-nolLD of different ages Figure 3 Comparison of mortality of RA-ILD VS RA-nolLD Figure 4 Comparison of mortality of RA-ILD morbidity types in previous literature statistics The prevalence of RA-ILD is 6.
52 patients per 100,000 inhabitants, and the incidence rate is 1.
04 patients per 100,000 per year
.

In this study, the total population included 173138 RA patients, of which 4330 (2.
5%) had clinical ILD
.

In the non-matched population, the mortality rate was 1.
71 per 100,000 residents, and the mortality rate remained stable over time during follow-up (Figure 1).
Compared with RA-noILD patients, RA-ILD patients have a higher risk of death, of which 65 years old The following patients have the greatest increased risk of death (Figure 2)
.

After controlling for factors such as age, gender, age of onset of RA-ILD, duration of RA, diabetes, arterial disease, dyslipidemia, and heart disease, Dr.
Pierre found that the adjusted mortality risk of RA-ILD patients was that of RA-nolLD patients.
3 times (Figure 3), and when the onset of ILD precedes RA, the risk of death in RA-ILD patients is higher (Figure 4)
.

Finally, the research team compared the treatment prescriptions of RA-nolLD patients with RA-ILD patients (matched population) and found that RA-ILD patients tend to receive less methotrexate (MTX), more biological DMARDs and more Corticosteroid treatment
.

3.
In recent years, the RA comorbidities and mortality in Western Australia have shown a downward trend.
The third academic report was lectured by Dr.
Khalid from the University of Western Australia School of Medicine.
Dr.
Khalid and his collaborators used the Western Australian Health Administration Data Set (Western Australian Hospital Incidence data, emergency department data and death registration in Western Australia), 17125 RA patients (ICD-9-CM 714.
0-714.
9 and ICD-10-AM M05.
00-M06.
99) were tracked, and the age-adjusted RA patients The overall mortality rate was 2.
5 times that of the general population during 1980-2015 (95%CI: 2.
52-2.
65), and 1.
5 times (95%CI: 1.
39-1.
81) during 2011-2015
.

In an RA cohort of 356,069 patients, 8955 (52%) died
.

According to statistical analysis, the main causes of death were 2386 people with cardiovascular disease (26.
6%), 1511 people with cancer (16.
8%), 519 people with rheumatism (5.
8%), 491 people with chronic lung disease (5.
5%), and 269 people with dementia (3.
0%).
And 235 people (2.
6%) with diabetes (Figure 5)
.

Figure 5 The main cause of death in RA patients The research team used the Chalson Comorbidity Index (CCI) to determine comorbidities, and calculated the mortality rate per decade (MRR) between the RA cohort and the general population of Western Australia through a direct age-standardized method.
And to evaluate the trend of comorbidities and hospital mortality per 1000 hospitalized patients for 30 consecutive years
.

The results of the study showed that RA comorbidities and mortality rates in Western Australia were -0.
5% and -4.
8% per year from 2001 to 2010, and -4.
4% to -2% per year from 2011 to 2015.
Dr Khalid believes this reflects Improved management of RA and comorbidities
.

4.
Early intervention is beneficial to reduce the cardiovascular risk of RA patients.
The fourth academic report was lectured by Dr.
Kazuki from Brigham and Women's Hospital in the United States.
Dr.
Kazuki and his collaborators used CorEvitas (formerly Corrona) from the United States.
October 2001 The data of RA patients registered as of May 2019 will record the Clinical Disease Activity Index (CDAI) from their first visit to the end of follow-up or the end of the first CV event
.

During this period, disease activity was measured according to CDAI (high, medium, low, and remission) classification every 6 months, and major adverse cardiovascular events (MACE) were recorded
.

MACE is defined as non-fatal myocardial infarction, non-fatal stroke (excluding transient ischemic attack) and cardiovascular death
.

A total of 40,721 patients in this study were eligible for analysis
.

After controlling for baseline confounding factors, MSM analysis and evaluation concluded that a higher CDAI will have a greater adverse effect on CV during the early follow-up period compared with the remission period
.

The research team predicts that the MACE-free curve will improve with the earlier transition to continuous relief for two reasons: 1) time; 2) HRs that change over time
.

Figure 6 The effect of CDAI on CV over time.
These findings indicate that the effect of RA disease activity on CVD is more prominent in the early stage of the disease.
Therefore, it can be expected that the reduction of early invasive disease activity will benefit the cardiovascular system more.
There is a treatment window to reduce future CV events in RA patients
.

Fives.
In recent years, the risk of additional heart failure in RA patients has decreased.
Heart failure (HF) is one of the most common cardiovascular diseases in RA patients
.

Previous studies have shown that compared with the general population, the risk of RA developing HF is 2 times higher
.

In order to further study the trend of the incidence of HF in RA patients over time, Dr.
Elena and his collaborators conducted this population-based cohort study of the incidence of RA
.

The study population included residents of Olmsted County, Minnesota with RA (age ≥18 years old, meeting the 1987 ACR criteria from 1980 to 2009) and non-RA subjects with the same basic population and similar age, gender, and historical indicators The person
.

All subjects were followed up until death, migration or April 30, 2019
.

Use Framingham criteria to define sudden heart failure
.

The Cox proportional hazard model is used to compare HF events within ten years, adjust age, gender, and cardiovascular risk factors, and calculate the cumulative incidence of HF adjusted for death
.

Figure 7: The cumulative incidence of any heart failure events in RA and non-RA patients.
When comparing the risk of HF in RA and non-RA subjects, compared with the general population, the risk of HF in RA patients in the 2000s did not increase (HR 1.
14, 95%CI 0.
73-1.
78)
.

This is in contrast to the 2-fold increase in the risk of HF in RA patients in the 1980s (HR 2.
20, 95% CI 1.
44-3.
34) and the approximately 1.
5-fold increase in the risk of HF in the 1990s (HR 1.
54, 95% CI 1.
04-2.
29)
.

Figure 8 Statistics of the HF risk of RA patients and non-RA patients based on 10 years and HF subtypes.
Dr.
Elena specifically pointed out in Figure 8 that compared with the 1980s, the additional risk of HF for both RA and non-RA was reduced in the 2000s, of which HFpEF The trend is converging
.

six.
Early-stage RA patients receiving targeted therapy have a reduced risk of cardiovascular events within 5 years.
RA is associated with a higher risk of CVD, which may be due to underlying inflammation
.

It is currently uncertain whether the use of targeted therapy (T2T) in patients with early RA (ERA) can effectively suppress inflammation to reduce additional cardiovascular risks
.

In this regard, Dr.
Lin and Professor Tan from the Department of Internal Medicine and Therapeutics of the Prince of Wales Hospital, The Chinese University of Hong Kong, China conducted an observational study.
The study compared ERA patients managed through T2T strategies with non-RA with matching CV risk factors.
The population’s 5-year cardiovascular event (CVE) rate
.

The study used the database of the Clinical Data Analysis and Reporting System (CDARS) and the Asian Clinical Rheumatism System Targeted Therapy (CRYSTAL) Registry.
Between 2012 and 2016, ERAs with baseline disease duration less than 2 years were recruited from the registry Subjects, all subjects will be analyzed within 5 years from baseline
.

The study identified 261 ERA subjects and 783 matched controls, with an average age of 60+/-12 years, 78% were women, 18% were smokers, and 8%, 25%, and 22% had diabetes, respectively , Hypertension and hyperlipidemia
.

The study analyzed the predictive factors of ERA cardiovascular events as follows: Univariate analysis in 1ERA cohort.
Plasma atherogenic index (HR 10.
7, p<0.
02) and age (HR 1.
1, p<0.
02) are the most important non-RA in CVE Specific predictors
.

2 The multivariate analysis in the AIP and age-adjusted ERA cohort is shown in Figure 9 Figure 9 The multivariate analysis in the AIP and age-adjusted ERA cohort is finally summarized by Dr.
Lin: 1.
Within 5 years, match with cardiovascular risk factors Compared with the control, ERA patients managed by the T2T strategy did not experience excessive cardiovascular events
.

2.
This ERA cohort may underestimate the RA and CVD risk status of real-world ERA patients
.

3.
Longer duration of remission has a protective effect on cardiovascular events, and even DAS28 remission may be sufficient to protect CV
.

4.
Higher disease activity in the first year may increase the risk of cardiovascular events, but whether refractory RA has a higher risk of cardiovascular disease remains to be studied
.

5.
Poor baseline functional performance (higher HAQ score) is associated with a higher risk of cardiovascular events, which may be related to longer time and more severe disease activity, or more structural damage and lack of body Activities related
.

In addition, the reversibility of HAQ decreases as the course of the disease increases
.

Seven.
Analysis of the contradiction between blood lipids and cardiovascular risk in RA patients.
In existing studies, the association between cholesterol and CVD risk is weakened in RA, while those in the lowest low-density lipoprotein (LDL) group (<70mg/dl) Patients with RA may have unexpectedly high CVD risks
.

Researchers are still unclear whether RA patients with low LDL have a greater burden of plaque than patients with high LDL, and whether differences in RA inflammation or LDL oxidation lead to low LDL levels
.

To this end, Professor George from the University of California, Los Angeles School of Medicine and his cooperation did further research
.

The study included 150 RA patients without CVD symptoms or medical history, and evaluated for coronary atherosclerosis through computed tomography angiography
.

The results of the study are as follows
.

Figure 10 The relationship between LDL groups and SSS and CAC (left), the relationship between LDL groups after adjustment (right) §For Framingham-D/Agostino soore, statin use, DAS28-CRP, waist-to-height ratio and The use of bDMARD has been adjusted
.

*p<0.
05, **p<0.
01
.

Figure 10 shows that RA patients with low-density lipoprotein <70 mg/dl have higher segmental stenosis score (SSS) and coronary artery calcification (CAC) scores, and the adjusted OR for extensive or obstructive plaque is 2.
82 (1.
12-7.
17), p=0.
031
.

Figure 11 The association between LDL groups and RA-related inflammatory factors After adjusting for the use of Framingham D'Agostino and statins (Figure 11), the researchers found no difference in RA-related inflammation between the LDL group
.

Figure 12 The correlation between LDL particle composition and statin therapy (left); the correlation between each group of LDL and oxLDL and ApoB IC immune recognition (right) found after adjustment, Figure 12 (left) LDL<70mg/dl group Patients who did not receive statins showed higher LDL oxidation than the high-LDL group.
Figure 12 (right) patients with LDL<70mg/dl had higher oxLDL and apoB100 IgG IC
.

Figure 13 The correlation between Lp(a) content and LDL oxidation in the LDL group.
The composition of LDL particles includes LDL1, LDL2, LDL3, LDL4, Lp(ɑ) and IDL.
LDL oxidation is positively correlated, and it is especially obvious in the LDL<70mg/dl group (Figure 13)
.

In addition, Professor George also counted the association between LDL oxidation and cytoinflammatory factors.
There was no difference in RA activity, CRP, TNF-α, IL-17A or IL-17F among the LDL groups
.

However, the level of IL-6 in patients with low-density lipoprotein <70 mg/dl was higher than that of other groups, and IL-6 was associated with coronary plaque load (an increase of IL-6In by 1 SD resulted in an average increase in CAC-In of 0.
34, p =0.
048)
.

In this EULAR online conference on RA and its comorbidities, the presenters contributed wonderful academic sharing and discussions, and explored more research directions related to RA
.

Finally, the conference chairmen Tsutomu Takeuchi and Claire Daien thanked all the participants and audience again, and the conference ended successfully
.

Reference materials: [1]https://ard.
bmj.
com/content/80/Suppl_1/54.
1.
[2]https://ard.
bmj.
com/content/80/Suppl_1/54.
2.
abstract[3]https ://ard.
bmj.
com/content/80/Suppl_1/55[4]https://ard.
bmj.
com/content/80/Suppl_1/56.
2[5]https://ard.
bmj.
com/content /80/Suppl_1/56.
1[6]https://ard.
bmj.
com/content/80/Suppl_1/57[7]https://ard.
bmj.
com/content/80/Suppl_1/58.
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