”It is human nature to prefer new drugs, and it is logical that new drugs are easily favored by doctors and patients. However, in clinical practice, expensive new drugs may not be better than inexpensive old classical drugs in all aspects, and it is most important to use the right drug for the right purpose. The most effective, safest and cheapest drugs to treat diseases are what we doctors are looking for.
When going out for consultation, we often see that patients with lupus erythematosus (SLE) who have used morte-macrolimus (MMF) with unsatisfactory results are considered to have used the best medicine and done their best, not knowing that the patients have not used the most classic cyclophosphamide (CTX). Some arthritis patients have not used methotrexate (MTX) before they have used expensive biologics. Similar phenomena are becoming more and more common, and it is necessary to call for continued attention to the clinical research and application of classical disease-relieving antirheumatic drugs (DMARD).
A. New drugs may not be better than old traditional drugs
CTX is one of the classic drugs that has been “attacked” but not surpassed by Lou.
In the early 1990s, the topic of the superiority of cyclosporine A (CsA) over CTX in the treatment of lupus nephritis was often discussed in academic meetings, but in the late 1990s the manufacturers of CsA faded from their academic promotion because CsA was not superior to CTX in the treatment of lupus nephritis;
However, an international multicenter randomized controlled trial in 2007 for the treatment of lupus nephritis showed that MMF was not superior to CTX in terms of efficacy and safety, leading the manufacturer to stop the academic promotion of MMF in the non-transplant field and to withdraw the corresponding marketing department as of October 1, 2007.
In fact, both CsA and MMF are effective anti-rheumatic agents as immunosuppressants. the combination of MTX and CsA for rheumatoid arthritis (RA) is superior in strength to almost any other combination of DMARDs. MMF replaces CTX for lupus nephritis, not in terms of efficacy over CTX, but in terms of avoiding the gonadal toxicity of CTX. The key to the availability of novel drugs that provide effective weapons for clinical treatment of the disease is accurate targeting.
Biologic agents for RA are almost unprecedented in their recent efficacy. And some studies have shown their efficacy in halting lesion progression and even repairing damage. But its high price has led to the need for changes in U.S. health insurance policies in the near future. Even the strong U.S. health insurance industry cannot afford such expensive drugs, so our fledgling health insurance industry must be even more unaffordable.
Although biologics for RA are a revolutionary advancement in anti-rheumatic therapy, it is still emphasized that they can be used in combination with the classic anti-rheumatic drug MTX for better efficacy. All biological agents are only a key part of the pathological mechanism of arthritis inhibition. If they are not used in combination with classical cytotoxic immunosuppressants, there will be a rebound of the disease once the drug is withdrawn or anti-antibody production leads to drug failure.
II. Methotrexate (MTX)
MTX is the most widely used drug in the rheumatology department and has ranked first among the drugs prescribed by rheumatologists in the U.S. In recent years, MTX is a very inexpensive and ancient drug, which was introduced in 1948 and has been reported to be effective in treating psoriasis, psoriatic arthritis and RA since 1951. In 1971, the US FDA approved it for the treatment of psoriasis; in 1988, it was approved for the treatment of active RA.
Since then, MTX has been rapidly accepted by rheumatologists worldwide and has proven to be a DMARD with high efficacy, rapid onset of action, good tolerability, and a satisfactory benefit/toxicity ratio. today, MTX is used to treat not only RA but also other autoimmune-mediated rheumatic diseases, including dermatomyositis, SLE, and vasculitis. So far, and even for a considerable period of time in the future, MTX is an irreplaceable drug for the treatment of RA.
As the classical drug MTX is familiar to everyone, there is no need to discuss its routine use here. However, a recent clinical trial with evidence-based medical implications has confirmed the superiority of injectable MTX over oral MTX in the treatment of RA.
MTX can be administered either orally or by injection. It has been widely believed that both modes of administration have equal efficacy. However, it has been the author’s long experience that the efficacy of injectable MTX is significantly better than that of oral MTX. For more than a decade, our department has insisted on injectable administration during the induction phase of RA treatment.
In 2003, Kurnik et al [1] compared the bioavailability of oral and subcutaneous MTX in a Crohn’s patient population and found that the difference in bioavailability between oral administration and subcutaneous injection was greater, with a mean value of 0.73 and a 95% confidence interval of (0.62-0.86). In 2004, Alsufyani et al [2] examined 61 cases of juvenile patients who were ineffective with oral MTX or who could not tolerate the side effects. or intolerant of side effects in juvenile idiopathic arthritis switched to subcutaneous injections, with 76% of patients achieving improvement after 3 months and with lower side effects than oral administration.
In early 2008, the first multicenter randomized, double-blind controlled trial comparing oral and subcutaneous MTX for RA showed that subcutaneous MTX was significantly more effective than oral MTX, with no statistically significant difference in tolerability.
In recent years, international attention has been drawn to the superiority of injectable MTX over oral, and there have been multicenter randomized, double-blind controlled trials that have confirmed this hypothesis. Injectable MTX is mainly administered subcutaneously abroad, whereas intravenous injection is mainly used in China. The author reviewed the instructions for the injectable form of MTX, and the domestic form is not labeled for subcutaneous injection, while the foreign form is labeled for subcutaneous injection.
Although subcutaneous injection and intravenous injection have equal efficacy, the latter significantly increases the pain of patients, the risk of treatment, the labor of nurses and the cost of injection. We sincerely hope that subcutaneous injection of MTX will be available in China soon.
III. Cyclophosphamide (CTX)
CTX is one of the most commonly used immunosuppressants in rheumatology, and is a classic old drug that has been used clinically for half a century. In the treatment of severe rheumatic diseases, such as critical SLE, ANCA-associated microvascular vasculitis, it often has a life-saving effect; and for intractable diseases, it can reverse or stop the development of chronic lesions to a greater extent and prevent chronic organ failure. We are all familiar with the use of CTX and the prevention and control of infections, and here we will only discuss the ovarian toxicity and hemorrhagic cystitis of CTX.
1. The problem of ovarian toxicity: SLE occurs in women of childbearing age. With advances in therapeutics and improved long-term remission rates of the disease, the issue of protecting ovarian function in the treatment of SLE has become increasingly prominent. In severe SLE, especially WHO-IV lupus nephritis, CTX is the main agent for induction therapy. However, the ovarian toxicity of CTX is certain, and in some patients, the dose of CTX required to induce remission is sufficient to cause ovarian failure.
According to the literature and the author’s study, ovarian tolerance to CTX is related to cumulative dose, age and other factors [5]. With increasing age, the tolerated dose of CTX by the ovaries decreases. This needs to be recognized clinically, and the maximum cumulative dose of CTX should be limited according to age in order to effectively prevent ovarian failure. Here, the author proposes the hypothesis of “the relationship between age and ovarian risk dose of CTX” in order to reduce the incidence of ovarian failure.
The hypothesis is: “The cumulative CTX dose of 8 g is the risk dose to the ovaries at the age of 30 years. For every 1 year lower age, CTX can be increased by 1 gram; for every 2 years higher age, CTX needs to be decreased by 1 gram.” If we follow this hypothesis, the ovaries can tolerate 20 grams at age 18, 13 grams at age 25, 5 grams at age 36, and 3 grams of CTX at age 40, and after age 46, the ovaries can no longer tolerate CTX. however, after menopause, if the condition requires the use of CTX, there is no need to be concerned about ovarian toxicity.
This is only a hypothesis and the expectation is that following this hypothesis and limiting the cumulative dose of CTX by age will allow more than 90% of women with SLE to avoid ovarian damage from CTX. This is only a hypothesis to be modified and determined by further clinical studies.
2, the problem of hemorrhagic cystitis: a large amount of foreign literature shows that CTX treatment of rheumatic immune diseases can result in hemorrhagic cystitis followed by bladder fibrosis and bladder cancer. the probability of CTX treatment of rheumatic immune diseases inducing hemorrhagic cystitis is as high as 2%-40% abroad [6]. However, the side effects of CTX-induced hemorrhagic cystitis are hardly encountered by rheumatologists in China, which is a problem that deserves our deep thought and research.
The author is currently using a clinical epidemiological cohort study strategy to follow the risk of CTX-induced hemorrhagic cystitis with various dosing regimens. If it can be confirmed that this side effect is rare in the Chinese rheumatic disease population, some induction and maintenance therapies for CTX treatment of rheumatic immune diseases can be proposed that are different from those in the West, further improving the probability of remission of rheumatic immune diseases in China.
IV. Leigongteng preparation
Leigongteng is an effective drug used in traditional medicine for the treatment of rheumatic diseases in China. Although Leigongteng preparations have not yet entered the international market and are not yet recognized by Western clinicians. The anti-rheumatic effect of Radix et Rhizoma is superior to that of antimalarial drugs and salazosulfapyridine, and even to that of azathioprine.
The prominent side effect of tretinoin is gonadal toxicity, which can lead to premature ovarian failure and infertility with long-term use. Therefore, the indications for tretinoin preparations should be mainly rheumatism in the elderly after menopause, and the use of tretinoin in young patients needs to be limited to a course of treatment (e.g., 3 months). The next research focus of scholars engaged in the pharmacological research of Leigongteng should be how to bring Leigongteng preparations (e.g. Leigongteng polyglucoside) to the international market as a drug for the treatment of rheumatic diseases in the elderly.
Hopefully, we will not see in the future that foreigners who have obtained patent protection with the ingredients of Leigongteng will import them to China at high prices, while our use of our own traditional medical preparations becomes an infringement.
In conclusion, while we are heartened by the arrival of new drugs that add new therapeutic weapons to the clinic, we still need to pay attention to the clinical research and application of good classical medicines.