Advances in Chinese and Western medicine treatment of Crohn’s disease
Crohn’s disease (CD) is a chronic inflammatory granulomatous disease of the gastrointestinal tract of unknown etiology, which can involve any part of the gastrointestinal tract, mostly in the terminal ileum and the right hemicolectum; its clinical manifestations are characterized by abdominal pain, diarrhea, decreased body mass, fistula, and intestinal obstruction. In the early stage of the disease, the inflammatory reaction is the main manifestation, and during the progression of the disease in repeated attacks and remission, complications such as perforation, intestinal stricture, obstruction, and fistula formation can gradually appear.
The main treatment principles are to control the active disease, prevent and control complications, and improve the quality of life. With the in-depth research on the pathogenesis of CD and new drugs, there have been many advances in the treatment of CD. This article focuses on the treatment progress of Crohn’s disease in recent years.
1.General treatment and diet therapy
Smoking cessation is one of the extremely important measures. Emphasis on diet and nutritional supplementation, high nutrition, low or no dregs diet, folic acid, vitamin B2 and other multivitamins and trace elements. Studies have shown that the application of elemental diet (complete gastrointestinal nutrition) can give patients nutritional supplementation while controlling the activity of lesions, especially for small bowel CD without local complications.
Complete parenteral nutrition is only used for those with severe malnutrition, intestinal fistula and short bowel syndrome, and should not be applied for too long. Recent studies have shown that total parenteral nutrition and elemental diet in the intestine can not only increase the intake of nutrients in the body and improve the nutritional status, but also decrease the antigenic load in the intestinal lumen and reduce the inflammatory response, while improving the systemic nutritional status and helping the recovery of lesions.
Food allergen tests are emphasized. Recent clinical examinations have shown that many patients are not allergic to fish, shrimp and crab, but to starchy foods instead. So it is very important to do food allergen test.
2.Salicylic acid preparation
Salicylic acid preparations have a long history as the traditional first-line drugs for the treatment of patients with mild to moderate CD, mainly including salazosulfapyridine (SASP) and 5-aminosalicylic acid or mesalazine (5-ASA). the SP used as a carrier in SASP produces adverse reactions, including nausea, vomiting, headache, bronchospasm, rash, liver and renal impairment, leukopenia, hemolytic anemia, and peripheral neuropathy, etc.
There are newly developed 5-ASA controlled-release formulations, such as mesalazine, which release drug molecules in the terminal ileum and colonic localization and are suitable for maintenance therapy in patients with mild ileocolic type and CD remission. 5-ASA drugs have uncertain efficacy for remission maintenance.
3.Glucocorticoids
Glucocorticoids have good efficacy in controlling disease activity, but cannot be used for maintenance therapy. They are mostly used for moderate and severe patients of all types, as well as for mild and moderate patients who are ineffective to aminosalicylic acid preparations, mainly including traditional glucocorticoids (such as prednisone and hydrocortisone) and new glucocorticoids (budesonide).
Conventional glucocorticoids are the drugs of choice for inducing remission of moderate to severe CD, and 60% to 80% of patients begin to show effects 10 to 14 d after prednisone, but serious complications such as adrenocortical insufficiency, osteoporosis, hypertension, diabetes mellitus, peptic ulcer, infection, and psychiatric disorders can occur during long-term use.
In order to reduce the occurrence of adverse reactions, researchers have developed new glucocorticoids with high bioactivity and receptor affinity, which can be rapidly metabolized in the liver after absorption and hardly enter the macrocirculation, of which budesonide extended-release tablets are a typical representative. The drug is slowly released in the terminal ileum and ascending colon, and because 90% of the drug components are metabolized by the liver, systemic adverse effects are significantly reduced. Prednisone is more effective than budesonide for CD, but the incidence of adverse reactions is significantly lower with budesonide than with prednisone. The use of hormones generally adopts a gradual withdrawal program, while the rate of hormone reduction should be reasonably adjusted according to the patient’s response to treatment, and for some patients who show recurrent disease, hormone ineffectiveness or dependence during treatment, the addition of immunosuppressive drugs for combination therapy can also be considered. Glucocorticosteroids (including budesonide) are not recommended for maintenance treatment because they induce various adverse reactions.
4.Immunosuppressants
Immunosuppressants are mostly used in patients with refractory, ineffective or dependent hormonal therapy or with recurrent fistulae, and the common immunosuppressants include azathioprine (AZA), 6-mercaptopurine (6-MP) and methotrexate (MTX), which inhibit chemotactic neutrophils by blocking lymphocyte proliferation, activation and reactive cell mechanisms. AZA is converted into 6-MP after entering the body to exert its immunosuppressive effect, and 6-MP can also be applied directly, because of its slow onset of action, it is mainly used to maintain remission, for example, when used in patients with active CD, it is often combined with glucocorticoids to improve the efficacy.
MTX is an inhibitor of folic acid synthesis, which is effective in controlling the disease in patients with active CD and preventing relapse in remission, and can be used in the treatment of glucocorticoid-dependent or ineffective patients, as well as in patients with CD who are resistant to purine analogues. Immunosuppressants are prone to adverse effects on the digestive system (including nausea, vomiting, abdominal pain, diarrhea, stomatitis, dyspepsia, etc.), liver damage, bone marrow suppression, bone pain and other adverse effects, and blood tests and liver function must be reviewed regularly during use. Some patients cannot tolerate it because of the large side effects.
5.Biological agents
With the in-depth research on the pathogenesis of CD, the choice of clinical treatment drugs has also undergone a new transformation from traditional anti-inflammatory drugs to the use of biological agents gradually. At present, the main clinical anti-tumor necrosis factor agents used in the treatment of CD are the following: infliximab (IFX), adalimumab (ADA), tolimumab (Certolizumabpegol), natalizumab (Natalizumab), etc.
IFX is a mouse anti-human TNF-α chimeric IgG1 antibody with no dose-effect, and is currently the most effective and widely used anti-TNF-α antibody, as confirmed by Akobeng et al. in a clinical study that IFX showed good efficacy in patients with active moderate or severe disease, or with fistulae, or in patients for whom traditional drug therapy was ineffective. However, the use of IFX increases the incidence of infection, especially in those who use immunosuppressive agents in combination, and because of the immunogenicity of IFX itself, infusion reactions and hypersensitivity reactions may occur during treatment, and are therefore contraindicated in patients with pneumonia, tuberculosis, intestinal obstruction, and optic neuritis.
Although the early intervention of biological agents has a positive impact on disease course modification, the role of classical immunosuppressive therapy in long-term maintenance of remission remains irreplaceable. Many experts advocate the use of anti-TNF monoclonal antibodies in combination with immunosuppressive agents in the early treatment of patients with moderate to severe CD as a way to enhance the efficacy based on the results of clinical studies obtained with the combination of IFX and immunosuppressive agents in the treatment of CD The results of clinical studies have been published.
Although there are no comparative clinical trials comparing multiple anti-TNF agents, multiple biologic agents appear to have equal efficacy in maintaining remission. However, IFX has been on the market for the longest time and has more data from clinical studies and experience with its application in the treatment of CD [11].
6. antimicrobial drugs and probiotics
Microbial infections are considered to be a potential factor in the development of CD, and antimicrobial therapy should be aggressively used in patients with concomitant infections, severe disease, and CD with complications such as abdominal, inter-intestinal, and perianal abscesses and fistulas. The most commonly used clinical agents are metronidazole and quinolones (ciprofloxacin), the former of which inhibits the growth of anaerobic bacteria in the intestine and has immunosuppressive and leukocyte chemotactic effects, and is effective for perianal lesions; while ciprofloxacin is effective for fistulas.
Because both have more adverse reactions when taken for a long time, they are generally used clinically in combination with other therapeutic drugs for a short period of time. In case of concurrent severe infections, appropriate antibiotics, often advanced broad-spectrum antibacterial drugs such as meropenem, linezolid, etc., should be selected based on drug allergy testing. It is worth mentioning that metronidazole is considered to have immunomodulatory effects.
CD patients have an overproliferation of harmful bacteria in the intestine leading to dysbiosis, while probiotics colonize the human intestine, which can adjust microecological dysbiosis and prevent and treat diarrhea by competitively rejecting promiscuous bacteria, and some metabolites can also stimulate the body’s nonspecific immune function and enhance human immunity, which play a synergistic role in maintaining CD remission and are mostly used for maintenance treatment of CD remission. Some authors believe that nutritional support and probiotics have no effect on relapse in the maintenance period.
7.Chinese medicine
There is less basic research on this disease in TCM. Although there is no record of the name of Crohn’s disease in ancient Chinese medicine, there is a rich discussion on the treatment of similar symptoms of this disease and a full understanding of its etiology and pathogenesis. In Wang Ji’s “Surgery”, “vague pains in the tianshu, gangrene of the large intestine; slight rise of the flesh on it, carbuncle of the large intestine”. The strange effect of good recipe – leak diarrhea door: “leak, the meaning of leakage, sometimes loose discharge, or for labor to heal; diarrhea, a moment of water to go as injection leak.”
The Golden Horoscope summarizes “intestinal carbuncle, swollen and swollen abdomen, painful like gonorrhea, urination is self-regulating, fever from time to time, sweating, and vicious cold, the pulse is slow and tight, the pus is not yet formed, can be put down, when there is blood; pulse is flooded, the pus has become”. The first part of the medical door and volume: “redness and pain around the anus …… a pus out for anal canker.” In addition, in ancient medical books, there is often a disease called “cross bowel”, which means that the urine and feces are out of place, and so on. Therefore, according to its symptoms, it can be classified as “abdominal pain”, “diarrhea”, “intestinal canker”, “blood in the stool”, “anal fistula”, etc. The symptoms can be classified as “abdominal pain”, “diarrhea”, “intestinal carbuncle”, “blood in stool”, “anal fistula”, etc. Patients with severe refractory CD often have abdominal pain, diarrhea, intestinal canker sores, blood in stool and anal fistula at the same time.
Chinese medicine believes that this disease is mostly caused by feeling external evil, poor diet, emotional disorders and deficiency of internal organs. Most of them are a mixture of deficiency and actuality, and are accompanied by concurrent or combined evidence, while the key to the development of CD is the congestion of Qi and blood, the internal accumulation of dampness, and the deficiency of spleen and kidney.
The deficiency of internal organs is mainly due to spleen deficiency. When the spleen qi is damaged, dampness is generated from within, and when dampness is stagnant for a long time, it will be transformed into heat, which will cause dampness and heat to foment, stagnate between the intestines, and lose its conduction, and then fight with the qi and blood to damage the blood channels, which will cause the blood to stagnate, and the blood to fail and rot, and ulcerate internally. In time, it can also spread to the kidneys, the spleen and kidney deficiency, the deficiency of the evil love, entanglement difficult to heal. Therefore, the key to the pathogenesis of the disease is the presence of dampness, congestion of Qi and blood, and spleen deficiency. The two are mutually causative, that is, the dampness is embedded for a long time, damaging the spleen and stomach, and in turn, the spleen is deficient in transporting and transforming, and the dampness is generated from within, forming a vicious circle.
As stated in the book, “intestinal canker sores are caused by dampness, heat and blood stasis in the small intestine” and “sores depend on the spleen and earth”. Therefore, we believe that the cause of CD abdominal pain, diarrhea, blood in the stool, and anal fistula is mainly centered on the pathology of the spleen and stomach, with the spleen and stomach reversing the lift and lowering, mixing the clear gas in the lower part of the body for food and diarrhea, and the earth deficiency and wood multiplying for abdominal pain.
”Cold, heat, dampness, food, gas, blood, etc. block the gastrointestinal tract and deplete the spleen and stomach, causing pain if it does not pass, and over time it will lead to accumulation and intestinal canker. Therefore, treatment should be based on strengthening the spleen, benefiting qi and cultivating the earth, supplemented by resolving pus, dispelling dampness, moving qi and invigorating blood. Main formula: Tonifying Zhong Yi Qi Tang plus reduction.
It has been used for nearly a thousand years and is one of the ten most famous prescriptions in Chinese medicine. It is composed of Astragalus membranaceus, Ginseng, Rhizoma Atractylodis Macrocephalae, Radix et Rhizoma Glycyrrhizae, Radix Angelicae Sinensis, Pericarpium Citri Reticulatae, Radix et Rhizoma Bupleurum and Radix et Rhizoma Chai Hu. Astragalus benefits Qi as the ruler, Radix et Rhizoma Ginseng, Atractylodes Macrocephalae strengthen the spleen and benefit Qi as the minister, Angelica nourishes Blood and invigorates Blood, Chen Pi regulates Qi and resolves phlegm, and Sheng Ma and Chai Hu elevate Yang Qi. The whole formula works together to raise Yang and lift Qi, strengthen the Spleen and benefit Qi, and activate Blood and regulate Qi.
The diagnosis and treatment plan of the Gastroenterology Committee of the Chinese Society of Integrative Medicine classifies ulcerative colitis into six types, including damp-heat in the large intestine, weakness of spleen qi, deficiency of spleen and kidney yang, deficiency of liver and spleen, deficiency of yin and blood, and spleen cold and intestinal heat. The clinical practice can refer to the above classification and select the corresponding treatment.
Summary.
In the treatment of CD, the most direct and effective means for CD patients is to standardize the rational use of drugs. CD is the most important cause of precancerous intestinal tumors and is several times more likely to become cancerous than general intestinal neoplastic polyps, especially in patients with long-term CD. It is important to be vigilant and make necessary examinations in order to get reasonable treatment in time.
Among all treatments, the aim of CD treatment is to control disease activity, relieve symptoms and prevent complications. The selection of therapeutic drugs should be based on the site of onset, activity, duration of disease and the presence of complications, and individualized treatment plans should be developed based on the patient’s past medication history, adverse effects and the presence of extraintestinal manifestations.
In recent years, the treatment of CD is gradually changing from traditional drug therapy to immunomodulatory biological therapy. When choosing various drugs for treatment, attention should be paid to the toxic side effects of the drugs. Chinese medicine also plays a significant role in CD disease control, maintenance treatment during remission, and promotion of body recovery.