New weapons have been added to the field of RA treatment, and new ideas for selective JAK inhibitors to unlock RA relief. Rheumatoid arthritis is a chronic, highly disable autoimmune disease. According to preliminary estimates, there are about 5 million RA patients in my country.

* is for medical professional reading only for reference

RA treatment field adds another powerful new weapon, and selective JAK inhibitors unlock new ideas for RA relief.

Rheumatoid arthritis (RA) is a chronic, highly disabling autoimmune disease. According to preliminary estimates, there are about 5 million RA patients in my country. RA is the most common clinical manifestation of joint swelling and pain. The condition is often repeated and gradually worsening, which eventually leads to joint structure damage and causes disability ^[1]. RA not only causes a decrease in the physical function, quality of life and social participation of patients, but also brings huge economic burdens to patients' families and society ^[2].

There is currently no cure for RA. Exploring reasonable treatment strategies and efficient treatment methods to improve the clinical remission rate of RA and improve patient prognosis has always attracted much attention from the rheumatism and immunology community. Today, Professor Zhang Zhiyi, director of the Department of Rheumatology and Immunology at the First Affiliated Hospital of Harbin Medical University, took us to deeply explore the current status and difficulties of RA treatment and how targeted treatment can help improve the clinical remission rate of RA.

RA clinical response rate is not optimistic.

targeted therapy may be a breakthrough

In recent years, with the advancement of early identification, disease evaluation, treatment strategies in the field of RA, and the application of new drugs, the prognosis of RA patients has been greatly improved, and clinical response has become an achieveable goal ^[3]. At present, early treatment and compliance treatment are the most important treatment strategies for RA, and clinical remission is the primary goal of RA treatment. For patients with long-term disease courses, low disease activity can be selected as the alternative treatment target ^[4].

However, some RA patients are still unable to achieve clinical remission, and they have not even achieved low disease activity ^[3]. In the Asia-Pacific region, the RA remission rate is low, and the remission rate varies among countries ^[5]. The treatment of RA compliance in my country is far from enough, and the clinical remission rate is not ideal ^[6]. CREDIT registration data shows that Chinese RA patients were treated with traditional synthetic anti-rheumatic drugs (csDMARDs) for 3 months, and 55% of patients had insufficient improvement in their condition; treated with csDMARDs alone for 6 months, and up to 60% of patients did not meet the treatment target ^[6]. It is urgent to find efficient and safe treatment options to improve the clinical response rate of RA.

It is gratifying that with the rapid progress of targeted therapy, more and more RA patients have been controlled and even completely relieved, and their prognosis has been significantly improved. A multicenter, real-world study in the Asia-Pacific region shows that the use of biological agents DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) is associated with higher clinical response rates of RA ^[5]. my country's 2022 edition of RA diagnosis and treatment standards point out that if csDMARD has improved disease activity for 3 months or has not met the standard for 6 months, and has combined with adverse prognosis factors, bDMARD or tsDMARD should be used as early as possible to treat ^[4]. The 2019 EULAR Guidelines also recommend that those who have not met the standard for initial csDMARDs and have combined with adverse prognosis factors, bDMARDs/tsDMARDs should be used to treat ^[7]. Therefore, targeted therapy may become an important breakthrough in improving the clinical remission rate of RA.

selective JAK inhibitor is shining,

unlocks new ideas for RA relief

reviews the history of the development of RA targeted therapy. From bDMARDs to tsDMARDs, RA's targeted therapy methods have been continuously enriched, promoting the upgrading of RA treatment goals. JAK inhibitors belong to tsDMARDs. Unlike bDMARDs that inhibit a single inflammatory factor, JAK inhibitors can simultaneously inhibit multiple inflammatory factors ^[4], which rely on the JAK pathway, providing new treatment options for RA patients.

JAK family includes 4 subtypes of JAK1, JAK2, JAK3, and TYK2, ^[8-10]. Previous JAK inhibitors are mostly non-selective inhibitors, which have been proven to be effective in controlling RA conditions, but there are also safety risks, such as anemia caused by excessive inhibition of JAK2 [11]. Selective JAK inhibitors can maintain efficacy and improve safety in principle. Selective blockade of a JAK subtype can inhibit specific biological functions while allowing other JAK-dependent cytokine to signal normally ^[11]. Therefore, the research and development of selective JAK inhibitors has become an important trend at present.

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

selective JAK inhibitor landed in China,

RA treatment adds a new tool

March 25, 2022, National Medical Products Administration (NMPA) approved uppatinib sustained release tablets for the treatment of moderate to severely active RA adult patients with poor response or intolerance to one or more TNF inhibitors. This marks that uppatinib sustained release tablets have become the first and only selective JAK inhibitor approved for the treatment of RA in my country, 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, we have found that uppatinib sustained release tablets have excellent performance in the field of RA treatment, and can take into account both efficacy and safety.

■ comprehensively and lastingly improve the response rate: The continuous long-term extension (LTE) study of the

SELECT-COMPARE study evaluated the long-term efficacy of uppatinib sustained release tablets and adalimumab in RA patients for 3 years. The results showed that the proportion of patients who reached CDAI≤10, CDAI≤2.8, DAS28-CRP3.2, and DAS28-CRP2.6 in the uppatinib sustained release tablets combined with methotrexate group at weeks 26, 48, 72, 120, and 156 in the 120th and 156 in the 156th. This means that uppatinib sustained release tablets can achieve better clinical remission and low disease activity compared with adalimumab, and the efficacy can last for 3 years.

Figure 1: During the 3-year treatment period, the proportion of patients who reached CDAI ≤10, CDAI ≤2.8, DAS28-CRP3.2, and DAS28-CRP2.6

#P0.05, ##p0.01, ###p0.001

■ is also excellent among Chinese people:

A study evaluated the efficacy of uppatinib sustained release tablets combined with csDMARDs in the treatment of RA patients with poor response to csDMARDs in China, South Korea, and Brazilian . Finally, 114 Chinese patients, 29 Korean patients were included in the group of uppatinib sustained release tablets combined with csDMARDs, and 26 Brazilian patients [13]. The results showed that after 12 weeks of treatment, the proportion of patients who reached DAS28-CRP2.6 and CDAI ≤2.8 in the uppatinib sustained release tablets combined with csDMARDs group was higher than that in the placebo and csDMARDs group (Figure 2) ^[13]. This shows that uppatinib sustained-release tablets can also achieve high remission rates in RA patients in China, South Korea and Brazil.

Figure 2: The proportion of patients who reached DAS28-CRP2.6 and CDAI≤2.8 for 12 weeks of treatment

*p≤0.05, ***p≤0.001 vs placebo; [*]p≤0.05, [**]p≤0.01, [***]p≤0.001, the p value with the band is nominal value (uncorrected for multiplexity)

■ Long-term safety tolerance:

SELECT-COMPARE study shows that the overall safety of uppatinib sustained-release tablets in RA patients is basically similar to adalimumab ^[14], and subsequent LTE studies found that uppatinib sustained-release tablets in RA patients for 3 years without new safety risks ^[12]. Safety data for up to 4.5 years also confirmed that the safety of upatinib sustained-release tablets for upa 4.5 years is similar to that of adalimumab and methotrexate , and did not significantly increase the risk of adverse events ^[15].

Nowadays, RA compliance treatment in my country is far from enough, and the clinical remission rate is still not optimistic. The application of targeted therapy is expected to improve the clinical remission rate of RA. As the first and only selective JAK inhibitor approved for RA indications, uppatinib sustained release tablets can comprehensively and last longer improve the clinical remission rate of RA and also show high remission rates in the Chinese population, with good long-term safety and tolerance, providing a powerful new weapon for RA treatment in China.

Expert Profile

Professor Zhang Zhiyi Doctoral supervisor

• First Affiliated Hospital of Harbin Medical University Director of the Department of Rheumatology and Immunology

• Deputy Director of the Institute of Infection and Immunology, Chinese and Russian Medical Research Center, Heilongjiang Academy of Medical Sciences

• Chinese Medicine Member of the Standing Committee of the Internal Medicine Branch

• Rheumatology Branch of the Chinese Medical Association The Ninth and Tenth Vice Chairman

• Honorary Leader of the Immune Purification and Cell Therapy Group of the Internal Medicine Branch of the Chinese Medical Association

• Chinese Medical Association Feng Vice President of the Wet Immunology Physicians Branch

• Leader of the Osteoarthritis Group of the Rheumatology Branch of the Chinese Medical Association

• Vice Chairman of the China Rheumatology Medical Alliance Alliance

• Deputy Chairman of the Osteoporosis Professional Committee of the Chinese Medical Education Association

• Deputy Chairman of the Rheumatology Professional Committee of the Chinese Rehabilitation Medical Association

• Deputy Chairman of the Rheumatology and Immune Disease Drug Research Committee of the Chinese Traditional Chinese Medicine Association

• Northeastern Province Rheumatology and Immune Disease Specialties Alliance

1 3

Heilongjiang Provincial Medical Association Chairman of the Rheumatology Association

• Heilongjiang Provincial Medical Association Rheumatology and Immunology Branch

• Heilongjiang Provincial Rheumatology and Immunology Disease Specialist Medical Alliance Alliance

• Five-year planning textbook "Internal Medicine" 7th edition , 8th edition, 9th edition editorial board

• 88-year planning textbook "Internal Medicine" 3rd edition editorial board

• "Chinese Journal of Rheumatology" editorial board

• " Chinese Journal of Internal Medicine " editorial board

• "Chinese Clinical Immunity and Rheumatism" Executive Editor

• "New Viewpoint of Rheumatism" (Chinese Version) Deputy Editor

• "Medical Reference News·Rheumatism Immunization Channel" Deputy Editor

• "ARD Magazine Chinese Version" Deputy Editor

• "Chinese Wolf" Associate editor-in-chief

• has won the Heilongjiang Province Outstanding Youth Job Expert

• has won the Heilongjiang Province Top Ten Outstanding Youth

• has won the first "Famous Doctor of the Country, Excellent Style" Award

References:

[1]Tian Xinping, et al. Chinese Journal of Internal Medicine. 2021; 60(07): 593-598.

[2] Rheumatology Branch of Chinese Medical Association. Chinese Journal of Internal Medicine. 2018; 57(4): 242-251.

[3] Smolen JS, et al. Nat Rev Dis Primers. 2018; 4: 18001.

[4] Geng Yan, et al. Chinese Journal of Internal Medicine. 2022; 61(01): 51-59.

[5]Sun X, et al. Lancet Reg Health West Pac. 2021; 15: 100240.

[6]Jin S, et al. Ann Rheum Dis. 2022: annrheumdis-2021-221841.

[7]Smolen JS, et al. Ann Rheum Dis. 2020; 79(6): 685-699.

[8]O'Shea JJ, et al. Ann Rheum Dis. 2013; 72 Suppl 2(0 2): ii111-5.

[9]Kiu H, et al. Growth Factors. 2012; 30(2): 88-106.

[10]Clark JD, er al. J Med Chem. 2014; 57(12): 5023-38.

[11]Schwartz DM, et al. Nat Rev Drug Discov. 2017; 17(1): 78.

[12]Fleischmann R, et al. RMD Open. 2022; 8(1): e002012.

[13]Zeng X, et al. Int J Rheum Dis. 2021; 24(12): 1530-1539.

[14]Fleischmann R, et al. Arthritis Rheumatol. 2019; 71(11): 1788-1800.

[15]Cohen SB, et al. presented at EULAR 2021. POS0220.

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