Rheumatism is a common and frequent disease, and the total prevalence rate is reported to be as high as 17.39% in China. Most of the current therapeutic drugs only inhibit the immune response non-specifically to reduce the rate of disease progression, with limited efficacy and large adverse effects, and doctors and patients are calling for the emergence of new drugs with good efficacy and low adverse effects.
With the increasing development of science and technology at home and abroad, new biologic agents targeting cytokines have been developed, which can specifically target an inflammatory mediator and block the progression of the disease, thus improving the prognosis of rheumatic disease patients. Biologic therapy has opened up a promising avenue for rheumatic diseases and has been included as one of the main elements of a new strategy for the treatment of rheumatic diseases in the 21st century.
A wide variety of biologic agents are available for the treatment of rheumatic diseases, including anti-CD4+ monoclonal antibodies, tumor necrosis factor antagonists [infliximab (infliximab), etanercept (etanercept) and adalimumab (adalimumab)], interleukin-1 antagonists (anakinra), gamma-interferon, co-stimulatory blocking factor ( abatacept) and anti-CD20 monoclonal antibody (rituximab).
Among them, tumor necrosis factor antagonists have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (including juvenile forms), ankylosing spondylitis, psoriatic arthritis, and Crohn’s disease due to their rapid onset of action, superior efficacy, delayed bone erosion, and fewer adverse effects. More than one million patients worldwide (the vast majority of them are rheumatoid arthritis) have been treated with these biologics, and there is a shortage of supply.
Drawing on foreign research results, China’s research and development of etanercept has also been introduced, which also unveiled the prelude to the application of biological agents for the treatment of rheumatoid arthritis and other major rheumatic immune diseases in China. The following we mainly introduce the tumor necrosis factor antagonists that have been used in clinical practice.
I. Biological role of tumor necrosis factor
Tumor necrosis factor is one of the most important cytokines in the pathogenesis of inflammatory arthritis, including rheumatoid arthritis, and its main biological roles include.
(1) Causing joint inflammation and cartilage destruction;
(2) Inducing the release of other inflammatory cytokines;
(3) mediating infection and sepsis, and participating in tumor surveillance, etc.
II. Introduction of tumor necrosis factor antagonists
1, infliximab (infliximab): trade name Remicade, developed by Johnson & Johnson, first approved by the FDA on November 10, 1999 for the treatment of rheumatoid arthritis, as the second FDA-approved anti-human tumor necrosis factor agents. It is the second FDA-approved anti-human tumor necrosis factor agent. It is a human-mouse chimeric (25% mouse protein and 75% human protein) IgG1k monoclonal antibody to tumor necrosis factor alpha, which inhibits the binding of tumor necrosis factor alpha to the receptor by binding biologically active soluble and membrane-bound tumor necrosis factor alpha.
The drug has a half-life of 8.0 to 9.5 days. For intravenous administration, the standard therapeutic dose is 3 mg/kg, starting with loading doses at weeks 0, 2 and 6, followed by maintenance therapy every 8 weeks. Within 24 hours of administration of the drug alone, patients experienced up to 60% reduction in clinical symptoms such as pain, morning stiffness and joint swelling. Because it is administered intravenously, allergic reactions can occur in 1% of patients.
In addition, repeated intravenous administration can produce anti-infliximab antibodies, but the simultaneous use of methotrexate (average dose of 7.6 mg/week) can reduce the production of antibodies, therefore, methotrexate is routinely used in combination in clinical practice.
2, etanercept: the trade name of Enbrel (domestic name Yicep, developed and marketed by Shanghai CITIC Guojian Pharmaceutical Co., Ltd. in 2005), developed by Amgen/Wyeth, was the first agent approved by FDA for the treatment of painful joint diseases on November 2, 1998. It is a synthetic soluble tumor necrosis factor alpha receptor fusion protein that specifically binds to tumor necrosis factor alpha and competitively blocks the binding of tumor necrosis factor alpha to tumor necrosis factor receptors on the cell surface, thereby blocking excessive tumor necrosis factor alpha in the body and inhibiting abnormal immune responses and inflammatory processes mediated by tumor necrosis factor receptors, but not lysing tumor necrosis factor alpha-producing cells. The long-term safety and efficacy of this drug has been demonstrated in a number of studies.
Its long-term safety and efficacy have been clinically demonstrated. It has a mean half-life of (102 ± 20) hours and is administered twice weekly at 25 mg subcutaneously in adults and 0.4 mg/kg in patients aged 4-17 years, with a maximum dose of 25 mg per dose to significantly reduce blood tumor necrosis factor levels. Etanercept can be used alone or in combination with methotrexate for the treatment of inflammatory arthritis such as rheumatoid arthritis. The most common adverse reactions are injection site reactions, infection, and headache. Injection site reactions include erythema and pruritus, which often disappear after 3 months of regular use.
3, adalimumab (adalimumab): trade name Humira, developed by Abbott/CAT, not yet available domestically, was approved by the FDA on December 31, 2002, for the treatment of moderately severe active rheumatoid arthritis that is not responding well to one or more anti-rheumatic drugs. Like infliximab, adalimumab is an anti-tumor necrosis factor alpha monoclonal antibody with clinical efficacy comparable to that of infliximab, but differs in that it is a fully humanized recombinant tumor necrosis factor alpha IgG1 monoclonal antibody that is less immunogenic than infliximab and rarely causes autoimmune-like syndrome.
It binds human tumor necrosis factor alpha with high affinity, disrupts cytokine binding to the receptor, and lyses cells expressing tumor necrosis factor alpha. The recommended dose of the drug is 40 mg once every other week by subcutaneous injection, either in combination with methotrexate or alone, or once weekly when used alone. Adalimumab is slowly absorbed, taking about 130 hours to reach peak concentration, with a half-life of 16 days.
Application of tumor necrosis factor antagonists in the treatment of rheumatic diseases
1, rheumatoid arthritis: clinical trials have confirmed that the use of conventional doses of tumor necrosis factor antagonists within 12 weeks, can significantly reduce joint symptoms, signs and experimental indicators have been significantly improved, so some people advocate that tumor necrosis factor antagonists can be used as some serious rheumatoid arthritis preferred to improve the condition of the drug. Of the three tumor necrosis factor antagonists, there is no evidence to suggest that one is more effective than the other, but if one of the agents is ineffective, switching to the other may be effective.
Adalimumab and etanercept can be used as monotherapy, while infliximab is best used in combination with methotrexate. The combination of methotrexate with one of these three agents produces significantly better clinical efficacy and arrests joint destruction than does the use of a single tumor necrosis factor antagonist. TNF antagonists may also be used in combination with cyclosporine A [2 mg/(kg・d)] or leflunomide or salazosulfapyridine.
In terms of economical and effective treatment strategy, tumor necrosis factor antagonists can be used in combination with another disease-modifying drug such as methotrexate at the beginning of treatment, and methotrexate alone can be used for maintenance treatment after 3 months to prevent joint damage and dysfunction.
2, ankylosing spondylitis: the U.S. FDA approved etanercept in 2003 for the treatment of severe active ankylosing spondylitis, the drug is the first biological agent approved for the treatment of ankylosing spondylitis. The FDA’s approval was based on a clinical study of 277 patients with ankylosing spondylitis, 58% of whom showed significant improvement in symptoms after six months of treatment.
The formulation resulted in significant improvement in signs, symptoms and laboratory indicators of ankylosing spondylitis within 12 weeks of treatment with regular doses. It can be used either alone or in combination with other second-line agents such as salbutamol or methotrexate. The efficacy of this agent has been reported to be maintained for up to 2 to 4 years. The approved dose of infliximab for the treatment of ankylosing spondylitis is 5 mg/kg every 6-8 weeks after induction, while the dose of etanercept is the same as for rheumatoid arthritis.
3. Psoriatic arthritis: Tumor necrosis factor antagonists provide rapid and significant relief of joint and skin lesion symptoms in patients with intractable psoriatic arthritis. One study treating patients with psoriatic arthritis with infliximab resulted in rapid and sustained improvement in skin psoriasis and a significant decrease in psoriatic lesion area and severity index scores. At week 16, all patients in the infliximab group had a reduction in severity index scores of more than 50%, with more than 1/3 of patients showing 100% improvement. In general, patients tolerated the tumor necrosis factor antagonist well.
Side effects of tumor necrosis factor antagonists
Since tumor necrosis factor may play a role in normal immune surveillance, inhibition of this cytokine may bring some adverse reactions as follows.
1. Infection: Infection is a more common and important adverse effect. More cases of tuberculosis have been reported in patients using infliximab and adalimumab than etanercept, such as 38 cases of tuberculosis in 150,000 patients treated with etanercept; 172 cases of tuberculosis in 198,000 patients treated with infliximab. However, it is still difficult to be sure which agent is at greater risk of causing tuberculosis.
Patients with rheumatoid arthritis were susceptible to tuberculosis (twice the baseline level), and the use of tumor necrosis factor antagonists increased the prevalence of tuberculosis further (four times the baseline level). Therefore, the use of use of tumor necrosis factor antagonists should be routinely screened with an antituberculin test and a chest radiograph. In addition, a small number of patients are at risk of inducing exacerbation of infection, and this type of drug should not be initiated or continued in those with severe or opportunistic infections, including septic arthritis, infected prostheses, acute abscesses, osteomyelitis, sepsis, or systemic fungal infections, but treatment may be resumed after infection control. The symptoms of hepatitis B and viraemia are aggravated in a small number of patients who use these drugs, so these drugs are not used for hepatitis B infection.
2. Injection site/static reactions: Adalimumab and etanercept administered subcutaneously cause more injection site reactions. Infliximab administered intravenously causes infusion reactions that are rare, and even if they do, they are mostly mild to moderate.
Tumors: Tumor necrosis factor plays a tumor surveillance role in several tumors. Inhibition of tumor necrosis factor may theoretically increase the risk of tumorigenesis, but there is no reliable evidence that such drugs increase the incidence of lymphoma and other malignancies or cause the recurrence of pre-existing solid tumors. The increased incidence of lymphoma in patients with highly active rheumatoid arthritis or ankylosing spondylitis itself is not related to the use of tumor necrosis factor inhibitors, but may be mainly related to the mutation of B cells under the long-term stimulation of chronic inflammation.
4. Neurological disorders: Only case reports of demyelinating-like syndrome, optic neuritis, transverse myelitis, multiple sclerosis and Parkinson’s disease have been reported. Patients with demyelinating disease or optic neuritis should not receive tumor necrosis factor inhibitor therapy.
5. Congestive heart failure: High-dose infliximab appears to be associated with a high relative risk of congestive heart failure and death, especially in patients with rheumatoid arthritis who have very poor cardiac function. Therefore, it is recommended that tumor necrosis factor antagonists should be avoided or used with caution in patients with rheumatoid arthritis whose congestive heart failure is poorly controlled.
6, other: individual cases of leukopenia, neutropenia, complete blood cytopenia, allergy, pericardial effusion, skin, systemic vasculitis and autoimmune-like syndrome, etc.. Some women become pregnant during the use of these drugs, but they do not differ from the normal population in terms of normal delivery, miscarriage and pregnancy termination rate.
In conclusion, tumor necrosis factor antagonists have been shown to be effective disease-modifying agents and are an important advance in the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and will likely be progressively extended to the treatment of other rheumatic diseases. Despite the potential for many of these adverse effects, the results of long-term open trials based on randomized controlled trials conducted at multiple research centers or national institutions since 2001 show that less than 10% of patients withdraw each year due to ineffective treatment or adverse effects, and that most of the patients included in the studies are patients for whom treatment with disease-modifying antirheumatic drugs is ineffective, suggesting that tumor necrosis factor antagonists are well tolerated The tolerability of tumor necrosis factor antagonists is still good. Patients can decide whether to use them according to the severity of their disease, the status of their co-morbidities and their economic status.