A new addition to the field of RA therapy is here, and selective JAK inhibitors are shining

*For medical professionals only

Rheumatoid arthritis (RA) is a chronic, highly disabling autoimmune disease, according to preliminary estimates, there are about 5 million RA patients ^{in China [1].}

RA is characterized by joint swelling and pain as the most common clinical manifestation, and the condition is repeated and gradually worsens, eventually leading to joint structural destruction and disability[^1].

RA not only causes a decline in patients' physical function, quality of life and social participation, but also brings a huge economic burden to patients' families and society ^[2].

At present, there is no cure for RA, and exploring reasonable treatment strategies and efficient treatment methods, improving the clinical remission rate of RA and improving the prognosis of patients has always attracted much attention
from the rheumatology and immunology community.
Today, Professor Zhang Zhiyi, Director of the Department of Rheumatology and Immunology, The First Affiliated Hospital of Harbin Medical University, takes us to an in-depth discussion of the current status and dilemma of RA treatment, and how targeted therapy can help improve
the clinical remission rate of RA.

The clinical remission rate of RA is not optimistic,

Targeted therapy may be a breakthrough

In recent years, with the advancement of early identification, disease assessment, treatment strategies, and the application of new drugs in the field of RA, the prognosis of RA patients has been greatly improved, and clinical remission has become an achievable goal ^[3].

At present, early treatment and standard treatment are the most important treatment strategies for RA, and clinical remission is the primary goal of RA treatment, and low disease activity can be selected as an alternative treatment goal for patients with long-term disease ^[4].

However, some patients with RA are still unable to achieve clinical remission or even low disease activity ^[3].

In Asia and the Pacific, RA response rates are low and vary between countries ^[5].

China's RA standard treatment is far from sufficient, and the clinical response rate is not ideal ^[6].

According to the data of the CREDIT registration study, 55% of RA patients in China were treated with traditional synthetic anti-rheumatic drugs (csDMARDs) for 3 months, and 55% of the patients had insufficient improvement; For six months of treatment with csDMARDs alone, up to 60 percent of patients did not meet their treatment goals ^[6].

It is urgent to find efficient and safe treatment options to improve the clinical response rate of RA
.

Fortunately, with the rapid progress of targeted therapy, more and more RA patients have been controlled or even completely remitted, and the prognosis has been significantly improved
.
A multicenter, real-world study in the Asia-Pacific region demonstrated that the use of biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) was associated with higher clinical response rates for RA ^[5].

。 China's 2022 version of RA diagnosis and treatment standards point out that csDMARD treatment improves disease activity by 50% < 3 months or does not meet the target for 6 months, and has adverse prognostic factors, bDMARD or tsDMARD should be combined with early</b12> treatment

Selective JAK inhibitors shine through,

Unlock new ideas for RA mitigation

Looking back at the development history of RA-targeted therapy, from bDMARDs to tsDMARDs, the targeted therapy methods of RA have been continuously enriched, which has promoted the upgrading
of RA treatment goals.
JAK inhibitors belong to tsDMARDs, and unlike bDMARDs that inhibit individual inflammatory factors, JAK inhibitors can simultaneously inhibit multiple inflammatory factors that rely on the JAK pathway ^[4], providing a new treatment option
for RA patients.

The JAK family consists of four subtypes: JAK1, JAK2, JAK3, and TYK2 ^[8-10].

Previous JAK inhibitors have mostly been non-selective inhibitors that have been shown to be effective in controlling RA, but there are safety risks, such as anemia due to excessive inhibition of JAK2 ^[11].

Selective JAK inhibitors can maintain efficacy and improve safety in principle, and selective blocking of one JAK subtype can inhibit specific biological functions while allowing other JAK-dependent cytokines to signal normally ^[11].

Therefore, the development of selective JAK inhibitors has become an important trend
.

Upatinib sustained-release tablets are a new type of drug customized for JAK1, which has high affinity and selectivity for JAK1, which can not only control inflammation by blocking key inflammatory signaling pathways such as IL-6, IFN-α, IFN-β, IFN-γ ^[8-11], but also avoid adverse reactions caused by inhibition of other JAK subtypes , bringing new hope
for RA treatment.

Selective JAK inhibitor landed in China,

The treatment of RA is another powerful tool

On March 25, 2022, the National Medical Products Administration (NMPA) approved upatinib extended-release tablets for the treatment of adult patients
with moderate to severe active RA who do not respond well to or tolerate one or more TNF inhibitors.
This marks that upatinib sustained-release tablets have become the first and only selective JAK inhibitor approved for the treatment of RA in China, bringing innovative treatment options to domestic patients, and is expected to help more RA patients achieve treatment standards and improve their quality of life
.

Throughout previous studies, upatinib extended-release tablets have excellent performance in the field of RA treatment, which can balance efficacy and safety
.

■ Comprehensive and lasting improvement of remission rate:

The SELECT-COMPARE study evaluated the long-term efficacy of upatinib extended-release tablets and adalimumab in patients with RA for 3 years, and the results showed that the upatinib extended-release tablet combined with methotrexate achieved CDAI ≤ 10, CDAI ≤ 2.
8, DAS28-CRP<3.
2, and DAS28-CRP < at weeks 26, 48, 72, 120, and 156 in weeks 26, 48, 72, 120, and 156 The proportion of patients in 2.
6 was higher than that in the adalimumab plus methotrexate group (Figure 1) ^[12].

This means that upatinib extended-release tablets can achieve better clinical remission and low disease activity compared with adalimumab, and the efficacy lasts for 3 years
.

Fig.
1: Proportion of patients who achieved CDAI ≤10, CDAI ≤ 2.
8, DAS28-CRP< 3.
2, DAS28-CRP<2.
6 during 3 years of treatment

#P<0.
05，##p<0.
01，###p<0.
001

■ Also outstanding in Chinese group:

In a study evaluating upatinib sustained-release tablets combined with csDMARDs in patients with RA who had poor response to csDMARDs in China, South Korea, and Brazil, upatinib sustained-release tablets combined with csDMARDs and placebo combined with csDMARDs included 114 Chinese patients, 29 Korean patients, and 26 Brazilian patients ^[13]
。 After 12 weeks of treatment, the proportion of patients in the upatinib sustained-release group combined with csDMARDs achieving DAS28-CRP<2.
6 and CDAI ≤2.
8 was higher than that in the placebo combined with csDMARDs group (Fig.
2) ^[13]
.
This shows that upatinib extended-release tablets can also achieve high response rates
in patients with RA in China, South Korea, and Brazil.

Fig.
2: Proportion of patients who achieved DAS28-CRP < 2.
6 and CDAI ≤ 2.
8 after 12 weeks of treatment

*P≤0.
05,****P≤0.
001 vs placebo; [*]p≤0.
05, [**]p≤0.
01,[***]p≤0.
001, p-value with [ ] is nominal (unadjusted for multiplicity)

■ Long-term safety tolerance:

SELECT-COMPARE STUDIES HAVE SHOWN THAT THE OVERALL SAFETY PROFILE OF UPATINIB EXTENDED-RELEASE TABLETS IN PATIENTS WITH RA IS BASICALLY SIMILAR TO ADALIMUMAB [14], WHILE SUBSEQUENT LTE STUDIES HAVE FOUND THAT UPATINIB EXTENDED-RELEASE TABLETS HAVE BEEN TREATED WITH IRA PATIENTS FOR THREE YEARS WITH NO NEW SAFETY RISKS^[12]
。 Safety data of up to 4.
5 years also confirmed that the safety profile of upatinib extended-release tablets for up to 4.
5 years was similar to that of adalimumab and methotrexate, and did not significantly increase the risk of additional adverse events ^[15].

Nowadays, China's RA standard treatment is far from enough, the clinical response rate is still not optimistic, and the application of targeted therapy is expected to improve the clinical response rate of
RA.
As the first and only selective JAK inhibitor approved for RA indications, upatinib sustained-release tablets can comprehensively and durably improve the clinical remission rate of RA, and also show high response rate in Chinese groups, with good long-term safety and tolerability, providing a powerful new weapon
for the treatment of RA in China.