Rheumatoid arthritis (RA) is a systemic disease with chronic inflammation of the joints as its main manifestation, and its pathogenesis is not yet fully understood, thus lacking specific clinical treatment measures. This has replaced the previous progressive pyramidal treatment model. The drugs now available for the treatment of RA include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, slow-acting drugs for disease relief (DMARDs), and biologic agents. The current status of RA treatment is reviewed in the relevant literature and is reviewed below.
NSAIDs are suitable for suspected RA or mild cases, and some patients can adequately control their symptoms with NSAIDs alone. There are more than 100 types of NSAIDs, which can be divided into:
(1) specific cyclooxygenase-1 (COX-1) inhibitors, such as aspirin, indomethacin, acetaminophen, etc;
(2) Inhibitors of COX-2, such as meloxicam, Aceclofenac, Nimesulide, Nedimetholone;
Specific COX-2 inhibitors, such as celecoxib, rofecoxib; valdecoxib, parecoxib, etoricoxib, etc. The main adverse effects of NSAIDs are:
Gastrointestinal symptoms, such as nausea, indigestion, abdominal pain, the incidence of gastrointestinal ulcers increases 2-3 times after 2-3 months of NSAIDS;
②Renal damage;
③ bone marrow suppression, mental disorders, etc.
2, glucocorticoids: Although glucocorticoids have many potential side effects, the short-term use of glucocorticoids in the early stage of the disease can quickly control the disease activity, often referred to as the “hormone bridge effect”. It has been shown that small doses of prednisone ≤10 mg/d can reduce the occurrence of joint damage in RA [8]. In addition to systemic administration, glucocorticosteroids can be given intra-articularly in patients with single joint swelling.
3, slow-acting anti-rheumatic drugs (DMARDs): these drugs can control the progression of RA disease, and should be used as early as possible in patients with early onset of symptoms < 3 months and a clear diagnosis of RA. DMARDs treatment is generally not less than 6 months, and the early use of DMARDs is effective.
Commonly used DMARDs drugs and their common doses are as follows: methotrexate (MTX) 12.5-25 mg/w, orally, by static push or intramuscular injection; salazosulfapyridine (SASP) 2-3 g/d, divided into 2-3 doses; leflunomide (LEF) 10-30 mg/d, orally; hydroxychloroquine (HAQ) 200-400 mg/d orally; cyclosporine (Cs) 2.5-5 mg/kg/d, divided into 2-3 doses. 5 mg/kg/d in divided doses; azathioprine (AZA) 2-3 mg/kg/d orally; gold sodium malate 50 mg/w start and gradually increase to 50 mg 4 times/week or oral preparation (Ryder) 3 mg in 2-3 times/d; penicillamine 500-1,000 mg/d orally; minotetracycline 200 mg/d in two oral doses. Among them, MTX, which inhibits folic acid synthesis, is most commonly used in the early treatment of patients with moderate to severe RA. The ACR20 can reach 50-60% with weekly MTX. MTX can delay joint damage. the main side effects of MTX are liver fibrosis, cirrhosis and interstitial lung fibrosis. Check liver function regularly and adjust MTX dosage according to liver function results. Leflunomide has a long half-life, and its excretion from the body can be accelerated by the use of abciximide once a toxic reaction occurs. Other DMARDs such as salazosulfapyridine, injectable gold and hydroxychloroquine do not have the long duration of action of MTX. These drugs can be used in certain clinical situations or in combination with other drugs. For example, salazosulfapyridine is commonly used to control mild to moderate disease activity and, like MTX, may relieve symptoms and slow joint damage. Cyclosporine, azathioprine, injectable gold, and penicillamine have all been shown to be effective, but their use is limited by toxic effects and risk/benefit ratios. Hydroxychloroquine and minotetracycline are mainly used for the treatment of mild patients.
4. Biological agents.
4.1 Tumor necrosis factor alpha (TNFα) blockers: The basic pathological change of RA is chronic synovitis. TNF is one of the major inflammatory mediators, which exists in various cells of RA synovium especially at the junction of blood vessels and cartilage, and not only participates in the synovial inflammatory response but also induces the destruction of joint structures.
4.1.1 Recombinant soluble TNF receptor fusion protein (Etanercept)
Etanercept is produced by recombinant gene expression in Chinese hamster ovary cells, consisting of 934 amino acids with a relative molecular mass of 150,000, and its mechanism is to compete with blood TNFa binding, block TNFa and cell surface TNF receptor binding, and reduce TNFa activity. The clinical application dose is 25mg, subcutaneously, twice a week. The efficacy of this drug in reducing the number of swollen and painful joints by 20% (20% ACR) was 59% after 1 month of treatment and 75% after 3 months of treatment in RA patients. Except for mild adverse reactions at the injection site, there was no other discomfort. In another clinical trial, the 20% ACR rate was 71% after 6 months in combination with methotrexate, compared with 27% with methotrexate alone (methotrexate + control drug). This shows that Etanercept has good efficacy and few adverse effects. Etanercept can also be used to treat methotrexate alone if it is not effective.
4.1.2 TNF monoclonal antibody Remicade
TNFa monoclonal antibody is a human/mouse chimeric IgG antibody. Remicade was approved by the FDA in November 1999 in combination with methotrexate for the treatment of patients with rheumatoid arthritis who have been incompletely treated with methotrexate, and in January 2001 the FDA approved Infliximab in combination with methotrexate to inhibit the development of joint damage in patients with rheumatoid arthritis. The efficacy of Remicade has been demonstrated in several studies of patients with rheumatoid arthritis. Common adverse effects include headache, diarrhea, rash, pharyngitis, cough, etc.
4.1.3 Soluble IL-1 receptor (SIL-1R) and IL-1 receptor antagonist (IL-1ra)
The intra-articular injection of human recombinant SIL21R and immunoglobulin fusion protein can compete with IL21 to inhibit the activity of IL21, which has been clinically proven to be effective in relieving symptoms. The adverse effect was a slight redness and itchiness of the injected skin.
4.1.4 Anti-IL-6 antibodies and anti-IL-6 receptor antibodies were used to treat patients with active severe RA with murine anti-human IL-6 neutralizing antibodies, and the number of joint pain, morning stiffness and painful joints were significantly improved, and the remission period could last for several months. Anti-IL-6 receptor antibodies were used to treat patients with refractory RA who were resistant to the slow-acting anti-rheumatic drug DMARD. 50 mg of anti-IL-6 receptor antibodies administered intravenously twice a week reduced CRP and ESR, and improved joint swelling, morning stiffness, and number of painful joints.
4.2 T lymphocytes are closely associated with RA because they represent the major cell subpopulation of synovial infiltrating cells. T cells, especially CD4+ T cells, have been shown to be involved in RA excitation and perpetuation. The fusion protein CTLA4Ig is a combination of the extracellular portion of the surface molecule CT-LA4 expressed by activated T cells and the Fc fragment of IgG. It has a small molecular weight, can diffuse, has a stronger affinity for B7 molecules than CD28, blocks the binding between CD28 and CTLA4 and its ligand B7, blocks CD28 co-stimulatory signaling, inhibits T cell value addition and differentiation into cytotoxic T cell lymphokines, induces a state of unresponsiveness to specific antigens, and has immunosuppressive effects both in vitro and in vivo.CTLA4Ig is CTLA4Ig is the most effective agent for blocking B7-CD28 co-stimulatory signaling. Therefore, CTLA4Ig is a promising drug for the treatment of RA.
4.3 Drugs acting on B lymphocytes: B cells are involved in the production of autoantibodies such as RF and anti-CCP antibodies in RA patients, and play an important role in RA. CD20, as a B lymphocyte surface membrane protein, is closely related to the transmembrane conductance of Ca2+ in B lymphocytes, and CD20 has a regulatory role in the proliferation and differentiation of B lymphocytes. As CD20 antibody, it can effectively inhibit B cells. Rituximab (rituximab), Zevalin and Bexxar are three types of anti-CD20 antibodies that have been approved for clinical treatment abroad, among which rituximab is a humanized chimeric anti-CD20 monoclonal antibody targeting CD20, and CD20+ B cells are its target cells. Rituximab was first approved by the FDA in 2006 for the treatment of refractory RA, and has good efficacy and safety. The CRP and RF levels decreased and imaging showed a reduction in synovitis and erosive destruction in those with significant treatment effects. The effectiveness of anti-CD20 monoclonal antibodies in the treatment of RA also suggests that B lymphocytes play an important role in RA synovitis.
4.4 Other T-cell receptor vaccines, human leukocyte antigen HLA-DRβ1 vaccine, HLA-DR4 peptide, CD28 monoclonal antibody, C II collagen peptide, etc. are still in various stages of research and are expected to be effective biologic therapeutic agents for RA.
In summary, the treatment of RA is currently advocated as early, regular and comprehensive treatment, and DMARDS should be used as early as possible (within 3 months), and more than one DMARDs should be used in combination with NSAIDs as early as possible, which is the so-called “inverted pyramid” scheme. NSAIDs only reduce symptoms in the early stage when DMARDs are not yet effective, but cannot control the progression of disease and bone destruction. The combination of hydroxychloroquine, salazosulfapyridine, and methotrexate is the international standard of treatment, and can be supplemented or replaced with leflunomide and biologics (alone or in combination) if ineffective or inefficient. Hormones can be added when there are systemic symptoms, and other immunosuppressive agents such as cyclophosphamide can be used for refractory and persistent RA. Biologic agents have a rapid onset of action, can be used in combination with other second-line drugs, do not produce systemic immunosuppression and fewer adverse effects, and will be a trend in the treatment of RA. Surgery should be considered when multiple DMARDs fail or when there is symptomatic and/or structural joint destruction. Hematopoietic stem cell transplantation and gene therapy are experimental studies and not included in conventional treatment, but may bring new prospects for RA treatment in the future. It is believed that in the future, medical practitioners will be able to develop the existing treatment methods, or develop another way to completely cure RA, and finally overcome this world-wide problem.