Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis and aggressive arthritis. In order to effectively control the disease and delay the destruction of joints, rheumatologists have conducted a lot of in-depth clinical research, and the treatment concept for RA has been updated. In recent years, many scholars have proposed the concept of “intensive treatment”, which has attracted widespread attention in academic circles [1].
I. The necessity of intensive treatment
The so-called “intensive treatment” is to develop an individualized early combined treatment plan based on the patient’s disease activity, and to closely follow up and adjust the medication according to the efficacy, so that the patient’s disease activity can be reduced to a preset level or achieve clinical remission within a certain period of time and prevent joint destruction and extra-articular injury.
Before the 1980s, the treatment model of RA was mainly based on an “upward ladder” regimen (or “pyramid” regimen), i.e., non-steroidal anti-inflammatory drugs (NSAIDs) were used as the initial drugs, and then disease-modifying drugs (DMARDs) were added one by one as the disease progressed. DMARDs). Clinical studies have found that this regimen provides symptomatic relief, but the long-term outcome is not satisfactory, with continued progression of imaging and inevitable joint destruction and deformity. The “window of opportunity” theory [i.e., the first 2 years of onset is the best time for RA patients to respond to treatment and should not be missed] has led to the gradual abandonment of this regimen and its replacement with the “downstep regimen The “downstep regimen” and the “sawtooth regimen” have been replaced by the “downstep regimen” and the “sawtooth regimen”, in which a combination of multiple DMARDs is regularly administered early and then tapered or sequentially maintained after remission. However, although this treatment strategy has suppressed inflammation to a certain extent and significantly delayed the progression of the disease compared with the “upper ladder” regimen, the benefits in terms of stopping bone erosion and destruction and reducing mortality are not ideal due to the ambiguous treatment goals and significant individual differences, so the “intensive treatment The concept of “intensive therapy” was born in this awkward treatment situation, and the application of biological agents has expanded and enriched this treatment concept.
Second, the elements of intensive therapy
1.Emphasis on early combination
More and more evidence shows that bone destruction of RA-involved joints is closely related to joint inflammation. Early control of joint inflammation and improvement of disease activity is the key to effectively stop joint bone destruction. There is a lack of clear definition and diagnostic criteria for early RA, however, joint magnetic resonance imaging (MRI) and the detection of autoantibodies such as anti-citrullinated polypeptide (CCP) and anti-keratin (AKA) antibodies can help in the early diagnosis of RA. In recent years, overseas studies have considered RA within 2 to 3 years as early RA, and these early patients have been treated with a combination of DMARDs or biologics, with a complete remission rate of more than 50%.
Intensive treatment, on the one hand, emphasizes early stage and, on the other hand, combination. Randomized clinical trials have confirmed that triple therapy is better than diphtherapy, and diphtherapy is better than monotherapy, such as the commonly used regimen of salazosulfapyridine plus hydroxychloroquine plus methotrexate is better than a two-by-two combination of these three drugs, which in turn is better than a single drug. In other words, RA should be treated as early as possible with two or more DMARDs in combination.
2, emphasizing individualization
Because rheumatoid arthritis is a heterogeneous disease, individual differences are large. Before treating patients, it is necessary to understand the patient’s age, gender, medication history, allergy history, disease activity and severity, the presence of combined osteoporosis, osteoarthritis or fibromyalgia syndrome, and even economic situation, etc. After a comprehensive determination, choose the most suitable drug combination for the patient to achieve the best efficacy and minimal adverse effects.
3.Adopt the standard control (tight control)
”The purpose of “target control” is to reduce inflammation or disease activity to a low level or achieve clinical remission within a certain period of time through active and effective treatment, in order to stop joint destruction and extra-articular damage. The TICORA study compared the efficacy and prognosis of “attainment control” with conventional treatment, with the goal of reducing DAS28 by 1.2 from baseline, or to less than 2.4, or achieving clinical remission (DAS28 <1.6) in RA patients within 2 years. The results showed that the "achieved control" group was significantly better than the conventional group, and that the "achieved control" group had a significant advantage over the conventional group in terms of imaging progression, joint function, and quality of life. Similar results were obtained in the CAMERA study. It is worth noting that in both studies, the "standard control" treatment was followed up once a month, compared to once every three months for conventional treatment. Thus, compared to conventional treatment regimens, "attainment control" means not only an intensification of the dosing regimen, but also an adjustment of the follow-up interval. The medication regimen can be changed in a timely manner according to the changes of the patient's condition, so that the treatment can be truly individualized.
The status of several drugs that can be used for intensive treatment
1.Methotrexate (MTX)
MTX has been used in the treatment of RA for more than 20 years, and has become the cornerstone of RA treatment with its positive efficacy, safety and reliability, and low price. A large number of clinical studies have shown that the long-term monotherapy efficacy of small doses (<20mg/w) of MTX is superior to that of other DMARDs. The combination of MTX-based DMARDs has become an accepted treatment option for RA in the rheumatology community. In many multicenter, randomized controlled studies of intensive therapy (e.g., TICORA, CAMERA, and BeSt), MTX has been included in combination regimens. Thus, both the American College of Rheumatology treatment guidelines and the European League Against Rheumatism treatment recommendations include MTX as the base drug for the treatment of RA. Even today, the advent of biologics has not diminished the place of MTX in the treatment of RA. On the contrary, numerous studies have confirmed that the combination of biologics and MTX can play a synergistic role in reducing the production of neutralizing antibodies to biologics and significantly delaying the imaging progression of RA, which is more effective than the monotherapy of both. Therefore, MTX is the core drug (anchor drug) of the intensive treatment regimen for RA, and the dose can be increased to 25-30mg/w if tolerated or required. 5-10mg/w of folic acid can be added to reduce its potential adverse effects.
2. Biological agents
Biologics have become a milestone in the treatment of RA, both in terms of relieving inflammation and blocking bone erosion. As a result, many countries have included biologics in the treatment guidelines for RA. Currently, there are five biologics approved for RA in the United States, including three anti-TNF-α antibodies [etanercept (etanercept), infliximab (infliximab), and adalimumab (adalimumab)], one T-cell-acting Abatacept (abatacept, a CTLA-Ig fusion protein), and one B-cell-acting Rituximab. Rituximab (rituximab) in B cells. Of these, TNF-α inhibitors are the most intensively studied.
Clinical studies have shown that TNF-α inhibitors are similar to MTX in relieving signs and symptoms, while they are superior in improving radiological progression, and the combination of the two is more effective than their respective monotherapy in treating early RA, with patients who respond poorly to MTX responding better to early addition of TNF-α inhibitors than to late addition, while intensive therapy with close monitoring and timely adjustment of therapy is more effective than conventional Intensive therapy with close monitoring and timely adjustment of therapy is more effective than conventional therapy. Recently, it has been demonstrated that the combination of TNF-α inhibitors and conventional DMARDs to induce remission at an early stage, followed by maintenance therapy with DMARDs, can also achieve good efficacy, and about half of the patients can stop using biological agents and maintain stable disease for more than 1 year.
3.Glucocorticoids
The use of glucocorticoids in RA treatment has been controversial, but based on the concept of “intensive treatment” of RA, short-term application of hormones in the early inflammatory stage can effectively control joint inflammation and suppress autoimmune reactions with the efficacy of NSAIDs or DMARDs, especially when rheumatoid vasculitis and extra-articular manifestations are prominent. In recent years, many foreign studies have used glucocorticoids as one of the drugs for intensive treatment of early RA. Overall, hormones should be used with caution in RA, weighing the pros and cons. For RA patients with severe disease or extra-articular manifestations, a higher dose of hormone (e.g., prednisone 40-60 mg/d) can induce rapid inflammatory remission and be reduced to less than 7.5 mg/d within 6 weeks, which can bring a good benefit/risk ratio, but long-term use of hormone over 10 mg/d should be avoided.
In conclusion, “intensive therapy” should be a new concept and trend in the treatment of RA now and in the future, and may help mankind to finally overcome this intractable rheumatic disease, which is worthy of reference by rheumatologists.