After the RA has been relieved, which drug should be taken first?

*For medical professionals to read and reference, the dry goods are full, quickly collect ~ In line with the original intention of "spreading the strongest rheumatism, creating a new academic fashion", at the time of leaving the old and welcoming the new, the "medical industry" media teamed up with the four top rheumatism in China Nearly 20 well-known experts in the field of rheumatism in the Department of Immunology, covering 8 hotspot diseases in the field of rheumatism, opened the "Rheumatism Annual Inventory in 2020".

In this issue, Professor Li Ru from Peking University People's Hospital brought us the latest developments in rheumatoid arthritis in 2020.

At the beginning of the conference, Professor Li Ru said that 2020 is an extraordinary year.
Although the new crown epidemic is raging around the world, the development of rheumatoid arthritis (RA) is unstoppable.

The new research on the RA mechanism is quick to see! First of all, the most prominent research on the mechanism of RA is the spectrum of RA pathogenic synovial cells.
Based on the application of single cell technology and synovial biopsy technology, researchers found that there are CD90+ synovial fibroblasts in the lower layer of RA synovial lining.
This group of cells It is considered to be the most important cell causing synovitis in RA, and other cells related to inflammation and immune activation have also been found, such as: IL1B+ proinflammatory monocytes; ITGAX+TBX21+ autoimmune-related B cells; PDCD1+ peripheral helper T cells (TPH); follicular helper T cells (TFH).

The study published in Nature found that THY1+ synovial lining sublayer fibroblast differentiation depends on Notch signal, inhibiting Notch3 to reduce arthritis, indicating that Notch3 participates in the inflammation of RA, and provides a new target for the treatment of RA.

The first study found that RA synovial fibroblasts have functional differences in different parts and phases, and have different phenotypes and characteristics.

The synovial fibroblasts of healthy people mainly play a supporting role, but play a destructive role in RA patients.

In different joints, synovial fibroblasts have different characteristics.

Studies have found that functional changes are related to epigenetic modification in the pathogenesis of RA.

Other mechanisms need to be further studied.

Diagnosis of RA, a lot of progress in PRIME cells-may predict the onset of RA? A study published in the New England Journal of Medicine in 2020 closely monitored 4 patients with RA and found that 1-2 weeks before the patients relapsed, there were activated autoreactive B cells in the peripheral blood, which induced CD45 -CD31- The PDPN+ phenotype of proinflammatory mesenchymal cells are called PRIME cells.
PRIME cells appear in the blood in the joints 1-2 weeks before the recurrence of RA patients, and then enter the joints to induce synovial inflammation.

Can PRIME cells predict the recurrence of RA in the future? This is a new research direction.

Figure 1: Compared with the classification standards of the American College of Rheumatology (ACR) and the European Union against Rheumatism (EULAR), PRIME cells have the highest diagnostic standard for early RA (ERA) classification.
The ERA classification standard has been confirmed by domestic and foreign studies to be very good for early RA Significance of the diagnosis.

Figure 2: ERA classification standard The study published by Professor Li Ru's team in "Clin Exp Rheumatol" in 2020 included three centers in China, Sweden and India, and found that ERA has the highest diagnostic standard compared with 1987 ACR and 2010 ACR/EULAR.

Table 1: Comparison of diagnostic criteria, especially for early rheumatoid arthritis with a course of less than 3 months, the sensitivity is better than the 1987 ACR standard, the specificity is better than the 2020 ACR/EULAR standard, and the AUC curve area is the largest.

Therefore, the ERA standard is very valuable for the diagnosis of early RA in international and domestic multi-center studies, and its clinical application is simple.

Figure 3: The course of the disease is less than 3 months.
The comparative new markers between ERA, 1987ACR and 2010ACR/EULAR are very valuable for the early diagnosis of RA ) It is highly expressed in the serum of RA, especially in the early stage of the disease within half a year, the positive rate of RA is 53%, in seronegative RA patients, the positive rate is 42%, and even before the onset of RA, there is a positive rate of 15%.
Before the onset of RA, the positive rate of SRA was higher than that of anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF).
Although there is no statistical significance between the three, it suggests that SRA is very valuable as an early diagnosis of RA .

There are multiple methods of treatment, but the advantages and disadvantages of the RA guideline update must be weighed to better guide the treatment of RA.
Professor Li Ru introduced the 2020 ACR release of the RA treatment guideline update (draft): Figure 4: RA treatment guideline A variety of biological agents, the treatment effect has its own merits.
There are clinically baritinib and tofacitib biologics for the treatment of RA.
A Meta-analysis study compared the efficacy of JAK inhibitors, adalimumab and MTX.
The study found that upatinib 15mg and baritinib The efficacy of Ni 4 mg is better than that of adalimumab, but the safety of adalimumab is the best.

A head-to-head study of upatinib and abatacept was published in the New England Journal of Medicine in 2020.
The primary endpoint is the change in DAS28-CRP.
The study shows that upatinib is superior to abasacept in reducing disease activity Pu, further comparing the number of joint swelling, tenderness, CRP and patient scores, upatinib has a significant effect on CRP, indicating that it has a better inhibitory effect on inflammation, but the adverse reaction rate of upatinib is higher than that Abatacept mainly had liver damage and 2 cases of venous thrombosis.

There are many drugs, and which biological agent should be preferred is still inconclusive.
A large registered study in the United States that included 4,816 cases compared the efficacy of tumor necrosis factor inhibitors (TNFi) and non-TNFi biological agents.
The two groups are in disease activity, There was no significant difference in remission rate, patient reported outcome, and functional score.
At present, there seems to be no significant difference in efficacy between the two groups of biologics. Early hormone therapy did not benefit.
The study published in The Lancet in 2020 used interleukin-6 (IL-6) inhibitors to induce remission.
When patients reached the DAS28-CRP state, the maintenance of the low-dose group was compared with hormone reduction The maintenance remission rate of the group was higher; however, another study showed that long-term treatment with low-dose hormones can increase the risk of infection in patients with stable RA.
This study is a cohort study of 170,000 cases.
The study found that even with hormones <5mg, Maintaining low-dose hormone therapy within 1 year increases the risk of infection.

Therefore, although low-dose maintenance hormone therapy can increase the remission rate, considering the risk of infection, it is not recommended to use low-dose hormones as long-term remission drugs.

Figure 5: Probability of infection with hormones for 1 year.
Adhere to T2T treatment and significantly improve the remission rate.
T2T can increase the sustained remission rate.
At present, T2T treatment is very recognized at home and abroad.

A study involving 10 countries showed that 38% of patients still did not follow T2T treatment, and further compared the effect of following T2T treatment on the sustained remission rate.
From the perspective of different remission standards, adherence to T2T treatment can significantly improve the remission rate.
Therefore, clinically, T2T treatment should be emphasized for RA patients.

Figure 6: Study results Table 2: The effect of following T2T treatment on sustained remission rate Another study found that compared with patients who did not adhere to continuous intensive treatment, continuous intensive treatment can increase the 5-year maintenance remission rate of patients, so it is necessary for RA patients It is said that continuous strengthening has certain help to the long-term prognosis.

What mitigation goal is better for the prognosis? A study compared a randomized controlled trial (RCT) study with a real-world study.
The RCT study is a more stringent remission state without joint swelling.
The results show that the prognosis of the RCT study is better than that in March, June, 1 year, and 2 years.
Real-world research, so stricter mitigation goals, better prognosis.

After RA reaches remission, which drug should be taken first? An RCT study was divided into two groups.
After the RA condition was relieved, one group reduced traditional synthetic disease-improving anti-rheumatic drugs (csDMARDs), and the other group reduced biological disease-improving anti-rheumatic drugs (bDMARDs).
After observation, it was found that the two groups were maintaining There was no statistical difference in remission rate. The drug-free remission rate of patients in the first reduction of csDMARDs group was slightly higher than that of the first reduction of bDMARDs group (20% vs 10%, P=0.
07).

A recent study involving 11 countries and 17 centers compared RA remission rates in the Asia-Pacific region and found that RA remission standards are different, and remission rates are also different.

Hong Kong, Kuwait and Japan have higher remission rates than other countries and regions.

Figure 7: The remission rate of RA in the Asia-Pacific region.
Further analysis of factors affecting remission found that women, patients with comorbidities, extra-articular manifestations, and combined use of hormones are not easy to achieve remission, and biological agents are a favorable factor for remission.

Table 3: Summary of factors affecting remission 1.
RA's pathogenic immune cell map has made a number of disruptive progress.

2.
New biomarker molecules provide a basis for early diagnosis and targeted intervention of RA.

3.
The draft of ACR's new RA guidelines was launched, which can be used as a reference for RA treatment options.

4.
New drugs with different mechanisms of action are successively available on the market, bringing new options for the treatment of RA.

5.
Low-dose hormones are a double-edged sword for RA treatment, and the application needs to be individualized.

6.
Standard treatment, continuous intensive treatment and stricter remission goals improve the prognosis of patients.

7.
Whether to reduce csDMARDs or bDMARDs first to achieve remission, there is RCT evidence published.

8.
The overall clinical remission rate in the Asia-Pacific region needs to be further improved.

Expert profile Professor Li Ru, chief physician of the Department of Rheumatology and Immunology, Peking University People’s Hospital, young member of the Rheumatology and Immunology Physician Branch of the Chinese Medical Doctor Association, editorial board member of the Rheumatology Channel of the Medical Reference News, Beijing Science and Technology Nova's main research direction is rheumatoid arthritis pathogenesis, diagnosis and He has published more than 50 academic papers in domestic and foreign journals, presided over or acted as a main researcher, undertook more than 10 national-level research work, and obtained scientific and technological awards as a main participant