Rheumatoid arthritis (RA) is a chronic autoimmune disease with synovial inflammation and joint bone destruction as its basic features. If not given timely and effective treatment, it can eventually result in the loss of function of the affected joints and seriously affect the quality of life and work ability of patients. Therefore, the treatment of RA has been one of the important issues of concern in rheumatology. From aspirin to specific COX2 inhibitors, from gold agents to a wide range of disease-modifying anti-rheumatic drugs (DMARDs), plus the much-praised glucocorticoids, the treatment of RA has gone through nearly a century of vicissitudes, and during this long journey, people have constantly updated their understanding of RA, and new therapeutic drugs and methods have emerged, especially the biologics developed in the last decade have brought the treatment of RA to a new level. In particular, the development of biologics in the last decade has pushed the treatment of RA to a new level, giving people reason to believe that RA is not an invincible disease. Zhao Yi, Department of Rheumatology and Immunology, Xuanwu Hospital, Capital Medical University
However, in the war against RA, it is not enough to rely on advanced weapons and equipment alone, but also requires more reasonable and effective combat strategies and methods. How to equip various weapons rationally, how to choose the best time point for attack and how to evaluate the battle situation timely and accurately to formulate the next attack plan, etc. will be important issues for us to think about in order to win this RA battle. Before the 1980s, people divided the drugs for the treatment of RA into first-line and second-line drugs, and gradually increased the drugs according to the progress of the disease using an upward ladder approach, but it was found that this treatment strategy was not ideal for improving RA disease, especially for stopping the progression of imaging. Subsequently, it has been recognized that the combination of multiple DMARDs started early in RA, known as the lower ladder regimen, can better mitigate the clinical progression of RA and slow down the bone destruction of the joint. The recent addition of biologics has further enriched this regimen, and the combination of biologics with MTX and other DMARDs has become the mainstay of RA treatment today. A large number of studies have shown that with the application of biologics, RA patients have significantly improved in terms of joint inflammation, bone destruction and quality of life.
Intensive therapy refers to the development of an individualized treatment plan based on the patient’s disease activity, close follow-up of the patient, and timely adjustment of the medication according to the treatment effect, with the goal of reducing the disease activity below a predetermined level or achieving clinical remission within a certain period of time [1].
Intensive treatment of RA should focus on the following aspects.
1. emphasizing the importance of early drug therapy
There is increasing evidence that bone destruction in RA-involved joints is closely associated with joint inflammation. Therefore, how to control joint inflammation early and improve disease activity is the key to effectively stop joint bone destruction. Since there is no clear diagnostic criteria or definition for early RA, clinical experience is particularly important, and anti-CCP antibodies, for example, can help in the early diagnosis of RA. In recent years, foreign studies have considered early RA as having a disease duration of 2-3 years or less, and these patients have been treated with DMARDs or hormonal or biologic agents on top of that, with a complete remission rate of more than 50%. This shows that in the early stage of RA disease, when the inflammation is not yet intense or when the inflammation has not yet caused damage to the bone, timely administration of sufficient amount of drugs to control the inflammatory response is extremely important to improve the prognosis of RA.
2. Intensive control of RA patients (tight control)
The purpose of intensive control is to reduce the disease activity to a low level or achieve clinical remission through treatment within a certain period of time. In recent years, several foreign studies have provided evidence for this. For example, the TICORA study compared intensive control therapy with conventional therapy. The aim was to reduce the DAS28 of RA patients to less than 2.4 or to achieve clinical remission (DAS28 <1.6) or a reduction of 1.2 from baseline within 2 years, and the results showed that the intensive control therapy group was better than the conventional therapy group for all three goals. Similar results were obtained in the CAMERA study. It is worth mentioning that in both studies, the intensive control group was followed up once a month, while the conventional treatment group was followed up once every 3 months. Therefore, compared with conventional treatment regimens, intensive control means not only intensification of the dosing regimen, but also closer observation intervals, so that the dosing regimen can be changed in a timely manner according to changes in the disease, thus achieving truly individualized treatment.
3. The place of methotrexate in RA drug therapy
Methotrexate (MTX) has been used in the treatment of RA for more than 20 years, and its efficacy, safety and reliability, and low price have made it the gold standard of RA treatment. Numerous clinical studies have shown that long-term monotherapy with small doses (<20 mg/w) of MTX is more effective than monotherapy with other DMARDs. The combination of MTX with other DMARDs has become the accepted treatment regimen for RA in the rheumatology community. Therefore, both the ACR's RA treatment guidelines and EULAR's RA treatment recommendations include MTX as the primary drug for the treatment of RA. Even the advent of biologics has not diminished the role of MTX, but rather, numerous studies have demonstrated that the combination of biologics and MTX is more effective than the two drugs alone. Many clinical multicenter, randomized, controlled studies of intensive therapy (e.g., BeSt, TICORA, CAMERA, etc.) have used MTX as the basic drug of treatment. Therefore, MTX is the core drug (anchor drug) in the intensive treatment of RA. Of course, for those patients who cannot tolerate MTX or are not effective in MTX treatment, they should promptly adjust the dosing regimen or switch to other DMARDs.
4. Application of biologic agents
Biologics (anti-TNFα, anti-IL-1 or anti-CD20 monoclonal antibodies) have become a milestone in the treatment of RA, with excellent performance both in reducing inflammation and in stopping bone erosion. As a result, biologics have been included in RA treatment guidelines in many countries. It is now widely accepted that if RA patients are not responding to MTX therapy for 3-6 months (including MTX in combination with other DMARDs), biologic therapy should be started as early as possible, which is an important component of intensive RA therapy.
5. On the use of glucocorticoids
The use of glucocorticoids in RA must be a topic of debate, but based on the concept of intensive RA treatment, short-term application of hormones at the early stage of inflammation has unparalleled effects for effective control of joint inflammation and suppression of autoimmune response by other NSAIDs or DMARDs drugs. However, it is generally advocated that a high dose (40mg-60mg/d) is used to induce inflammation remission at the beginning of hormone therapy, which is rapidly reduced to less than 7.5mg within 6 weeks, and long-term application of hormones >10mg/d should generally be avoided.
At present, although the intensive treatment about RA has been affirmed in several multicenter clinical trials abroad, the determination of its specific protocol and the evaluation of its long-term efficacy need more evidence-based basis. Moreover, how to develop a more clinically convenient intensive treatment program is also an urgent issue to be studied in the future. In addition, there are still some detailed problems in the development of intensive treatment protocols, such as the determination of early RA, the criteria of clinical remission, the evaluation system of treatment effect, and the inconvenience and side effects of intensive treatment to patients. In any case, the formation of intensive treatment strategy has sounded the call for the general attack for the final victory of human beings over RA, and it is believed that fruitful results will be achieved.
References
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