(Experts on the rational use of drugs): The common market consumption law of “cheap is not good, good is not cheap” is not suitable for clinical treatment, especially in rheumatology. The actual efficacy of several expensive anti-rheumatic drugs newly released in recent years has not surpassed that of the classic traditional old drugs. The most effective immunosuppressive drugs for the treatment of rheumatic immune diseases are still the very cheap prednisone, methotrexate, cyclophosphamide, etc. We need to accept and fully understand the characteristics of new and expensive drugs and their advantages, but it should also be clear that the latest does not mean the best, the most expensive drugs do not mean the highest level of treatment, and the most important thing in internal medicine treatment is to use just the right drugs.
First, the rational choice of oral hormones There are three kinds of oral hormones on the domestic market: prednisone, methylprednisolone and dexamethasone. Dexamethasone is a long-acting hormone, and although it has strong anti-inflammatory effects, it also has strong inhibitory effects on the hypothalamic-pituitary-adrenal axis and has large side effects on long-term use, so the rheumatology department opposes oral dexamethasone as a long course of anti-rheumatic treatment. However, it can be given intravenously for short-term intensive anti-inflammatory therapy or temporary use. The main choice for a long course of anti-rheumatic treatment is the medium-acting hormone prednisone or methylprednisolone.
In terms of price comparison, prednisone is $0.04/tablet and methylprednisolone is $1.20/tablet. Many doctors believe that the side effects of methylprednisolone are smaller than those of prednisone, so the more expensive methylprednisolone is preferred. In fact, this concept is not accurate. In Western countries, more than 90% of rheumatologists who prescribe oral hormones choose prednisone and rarely use methylprednisolone.
In terms of gastrointestinal side effects, prednisone is superior to methylprednisolone. Prednisone is a prodrug that has no biological activity in the gastrointestinal tract and needs to be activated in the liver as prednisolone in order to exert its pharmacological effects, with no direct irritation of the gastrointestinal tract. Methylprednisolone is an active drug and has a direct stimulating effect on the gastrointestinal tract. Therefore, the gastrointestinal side effects of prednisone are lower than those of methylprednisolone.
Problems in the liver. Prednisone is a prodrug that needs to be activated in the liver to prednisolone in order to exert its pharmacological effects. Therefore, some people are concerned about the side effects of prednisone on the liver, and the more expensive methylprednisolone is preferred, which is also inappropriate. The process of activation of prednisone to prednisolone in the liver does not damage the liver. Even in patients with combined hepatitis virus carriers or mildly elevated liver enzymes, the use of methylprednisolone is not superior to prednisone because mildly elevated liver enzymes do not affect the activation of prednisone, and prednisone does not damage the liver. Clinically, only patients with severe hepatitis and cirrhosis in the decompensated phase may affect the activation of prednisone and affect its biological effects. It is only in such patients that methylprednisolone or prednisolone is required to ensure its efficacy.
In addition, the author’s experience suggests that equivalent doses of methylprednisolone are more likely to produce side effects of Cushing’s syndrome such as full moon face compared to prednisone.
II. Methotrexate is safe, efficient and inexpensive Oral methotrexate is inexpensive, less than 5 RMB per month, and injectable methotrexate costs only two dozen RMB per month. According to the statistics of the top ten most prescribed drugs by rheumatologists in the United States, methotrexate has been ranked first for many years. Many doctors in the United States jokingly refer to rheumatologists as “methotrexate doctors”.
In terms of safety, there have been many large sample sizes and multicenter long-term follow-up studies showing that most patients can use methotrexate for long periods of time, for more than a decade or even decades. To date, no anti-rheumatic western drug is superior in terms of long-term safety. In terms of efficacy, methotrexate is currently the most effective drug for the treatment of rheumatoid arthritis and should be used as the base drug in all combination therapy regimens. In terms of single dosing. Methotrexate, which costs only a few dollars per month, is comparable in efficacy to biologics, which require more than $10,000 per month. Therefore, patients on biologics must be on methotrexate at the same time to get better results.
In the drug treatment of rheumatoid arthritis, methotrexate is a long course treatment. In recent years, rheumatologists in Europe and the United States have positioned methotrexate as an anchor drug for the treatment of rheumatoid arthritis. The implication of anchor drug is that methotrexate should be considered once the diagnosis is made and the drug is needed, unless there are contraindications. After the disease has been controlled, methotrexate should be tapered off before other drugs, unless methotrexate-related side effects occur.
According to the author’s experience in treating rheumatoid arthritis, the program for controlling the disease is: “subcutaneous methotrexate + small dose of hormone” for mild to moderate patients, which costs tens of dollars per month; for moderate patients, the classic combination therapy program “subcutaneous methotrexate + hydroxychloroquine + small dose of hormone” is recommended. For severe and rapidly progressive patients, “subcutaneous methotrexate + low-dose cyclosporine (50 mg, bid) + low-dose hormone” is recommended at a cost of more than 600 yuan per month; for persistent progressive patients with poor results of the above treatment, the use of “subcutaneous methotrexate + low-dose cyclosporine (50 mg, bid) + low-dose hormone” is considered. “subcutaneous methotrexate + biologics + low-dose hormones. For patients using biological agents, after controlling disease activity, the method of drug reduction and withdrawal is as follows: for patients using etanercept, reduce etanercept dose density by gradually extending the dosing interval to reduce the cost and reduce side effects; for infliximab users, withdraw the biological agents first after controlling the disease and switch to low-dose cyclosporine relay for an excessive period of time to prevent the disease after discontinuation of biological agents The first step is to withdraw from the biologic after controlling the disease and switch to low-dose cyclosporine for a period of time to prevent rebound after the biologic is stopped.
The inexpensive methotrexate is not only used in the treatment of rheumatoid arthritis, but is also an effective drug in the treatment of various autoimmune related rheumatic diseases. For the past ten years or so, the author has been using methotrexate for the treatment of various rheumatologic diseases such as mild to moderate lupus erythematosus, dermatomyositis, and vasculitis. In my opinion, for immune diseases requiring long-term hormone therapy, methotrexate can at least play the role of a hormone co-reducer; for severe lupus erythematosus and vasculitis, after cyclophosphamide induction therapy, methotrexate can be used as a follow-up therapy to replace cyclophosphamide, which is the opinion of rheumatologists in western countries to choose azathioprine, while the author believes that methotrexate is superior to azathioprine; for lupus erythematosus and For patients with lupus erythematosus and vasculitis not severe enough to warrant the use of cyclophosphamide, such as patients with lupus nephritis WHO-II, the author recommends the use of methotrexate and hormones rather than a single hormone.
In recent years, methotrexate has also been recognized in Western countries for the treatment of rheumatic immune diseases other than rheumatoid arthritis, including dermatomyositis, lupus erythematosus, and vasculitis, and such reports are gradually increasing. The author expects that within 5 to 10 years, international colleagues will recognize the importance of methotrexate in treating rheumatoid immune diseases other than rheumatoid arthritis.
III. The anti-rheumatic status of cyclophosphamide has not yet been shaken cyclophosphamide is currently the most effective drug for the induction therapy of severe rheumatic immune diseases, especially lupus nephritis and ANCA-associated vasculitis. It is also a very inexpensive anti-rheumatic drug, with each 200 mg injection costing as little as $6. Depending on the condition, the monthly dosage is usually 5 to 15 injections, or at most, no more than $100. Over the years there have been several manufacturers of the new immunosuppressants cyclosporine A, morte-macrolimus, and tacrolimus who have tried to replace cyclophosphamide with their products. However, all were eventually declared failures in rigorous randomized multicenter clinical trials. To date, cyclophosphamide, an inexpensive drug, remains sacrosanct in the treatment of severe rheumatic immune diseases.
The efficacy of cyclophosphamide is an accepted fact in the industry, and the main problem with clinical use of the drug lies in its toxic side effects. A good grasp of cyclophosphamide dosing techniques can maximize efficacy and minimize side effects.
The first problem is bone marrow suppression and infection. This problem is mainly related to the single dose or dose density, but not to the cumulative dose in the long term. In severe rheumatologic diseases for which cyclophosphamide is indicated, cyclophosphamide should be used decisively for treatment to induce remission if the disease is not of long duration, if the patient is still in good health, and if there are no signs of infection. Fatal infections due to cyclophosphamide rarely occur at this time, and even if myelosuppression occurs unexpectedly, the blood picture is mostly restored about 2 weeks after suspension of cyclophosphamide. Clinically, it is common to see severe rheumatic immune diseases that are delayed to severe hypoproteinemia and poor physical and nutritional status due to overly conservative initial treatment, over-reliance on high-dose hormones without immunosuppression, or too weak immunosuppression. This condition has a higher probability of serious infections.
The second is gonadotoxicity. The gonadal toxicity of cyclophosphamide is related to the cumulative dose, but not to the dose density. The key to avoiding gonadal toxicity is to control the cumulative dose. Cyclophosphamide can reduce sperm count and function in men, with severe cases of infertility, but less frequently impotence. In women, ovarian failure manifests as amenorrhea and early menopause. Tolerance of the ovaries to cyclophosphamide is related to cumulative dose, age and other factors. More than two years ago, the author proposed a hypothesis of “the relationship between age and ovarian risk dose of cyclophosphamide”, hoping to reduce the incidence of ovarian failure. The hypothesis was that “a cumulative CTX dose of 8 g is the ovarian risk dose at the age of 30 years. CTX can be increased by 1 gram for every 1-year decrease in age; for every 2-year increase in age, CTX needs to be decreased by 1 gram.” If this hypothesis is followed, 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.
Bladder toxicity of cyclophosphamide is not a problem in rheumatology in China. Foreign literature shows that the probability of inducing hemorrhagic cystitis with cyclophosphamide for rheumatologic diseases is as high as 2% to 40%. However, this side effect of cyclophosphamide is very rare in China, probably related to ethnic differences, and should only be observed clinically with care and should not be a barrier to drug use.
Long-term carcinogenesis is only a potential side effect. The long-term carcinogenic effect of cyclophosphamide mainly refers to the increased incidence of hematologic tumors, especially lymphomas, in the distant future. Some scholars estimate that the cumulative dose of cyclophosphamide is less than 10 grams, there is no long-term carcinogenic effect; the cumulative dose is more than 30 grams, the risk of carcinogenesis increases with the dose; if the cumulative dose exceeds 100 grams, the risk of carcinogenesis increases significantly, and some data show that the risk of lymphoma (RR value) is 10. Assuming that the prevalence of lymphoma is 1 per 1,000, an increase of 10 accompaniments is only 1 percent, while If a patient with rheumatologic disease, the cumulative dose of cyclophosphamide had to reach 100 grams, his condition would certainly be critical and persistent, and if not used its probability of death would be with much more than 1%. While doing research requires statistical significance, medication decisions require even more clinical significance. The author emphasizes that the cumulative dose of cyclophosphamide should be minimized in clinical antirheumatic therapy, but the necessary treatment should not be abandoned for fear of long-term carcinogenic effects.
IV. Antirheumatic effects of mortifamolates For severe rheumatic immune diseases such as lupus erythematosus and vasculitis, mortifamolates are less effective than cyclophosphamide and no less threatening to infection, while there is a more expensive price, so the author opposes mortifamolates as the drug of choice for the treatment of these diseases. The advantage of mortifamate over cyclophosphamide in the treatment of severe rheumatic immune diseases is its lack of ovarian toxicity. There are at least 2 clinical groups of patients with severe lupus nephritis who need to be considered for mortifamolates.
One is relapsing lupus nephritis. Lupus erythematosus is a disease that is prone to relapse, and if a larger cumulative dose of cyclophosphamide has been used for past induction therapy, it will most often lead to ovarian failure if cyclophosphamide induction therapy is used again. At this point, if mortification is switched to mortification, ovarian failure will be avoided.
Second, severe and more persistent lupus erythematosus. In cyclophosphamide induction therapy for lupus nephritis, there are some severe and more recalcitrant cases in which the disease has not yet reached remission and there is still a large amount of proteinuria and hypocomplementemia when its cumulative dose has approached the risk dose for ovarian. If cyclophosphamide is continued at this time, it will likely lead to ovarian failure; if immunosuppressive therapy is discontinued, it will lead to disease remission; if mortifamate is switched and induction therapy is continued, there will be a greater probability of preserving ovarian function and allowing the disease to continue to reach remission.
V. Selection of nonsteroidal anti-inflammatory drugs NSAIDs are proliferating and diverse, with similar effects. Rational medication decisions require a balance of safety, efficacy, and pharmacoeconomics, rather than a trendy selection of the latest selective COX-2 inhibitors, which are far more expensive than traditional NSAIDs, with no advantage in efficacy.
Patients with a history of peptic ulcer or gastrointestinal bleeding who have to use NSAIDs are recommended to choose selective COX-2 inhibitors, etoricoxib or celecoxib. The former has a strong anti-inflammatory and analgesic effect, but is slightly more expensive than the latter.
Combining efficacy and safety, the author believes that meloxicam is a better drug. According to the prescription statistics of rheumatologists in the United States, the NSAID celecoxib ranked first before 2007, while meloxicam ranked first after 2008. At present, the domestic meloxicam is more than 1 yuan per tablet, which is the NSAID with a relatively high letter price. In recent years, the author has prescribed more combinations of “1 tablet of prednisone in the morning and 1 tablet of meloxicam in the evening” for less than 2 yuan per day in anti-inflammatory analgesia.
For elderly patients who need to take into account cardiovascular safety, naproxen is a better choice. Foreign information shows that among NSAIDs, the best cardiovascular safety is naproxen, and the price is very cheap, just over 20 cents per tablet. However, the author’s experience suggests that its gastrointestinal reactions are slightly more than those of celecoxib and etoricoxib.
In conclusion, clinical anti-inflammatory analgesia needs to be individualized according to the characteristics of the drug, combined with specific patients, in order to achieve a safe and effective and economical medication concept.