Immune checkpoint inhibitors are currently used in lung cancer, and the data is relatively mature. So today I will share with you some adverse reactions that occur during the treatment of immune checkpoint inhibitors and our processing experience.

Article source: Dancing with Cancer/Speaker: Dr. Zhang Panpan/Compiled: Little White Rabbit is also sad

Immune checkpoint inhibitors are currently used more frequently in lung cancer, and the data is relatively mature. So today I will share with you some adverse reactions that occur during the treatment of immune checkpoint inhibitors and our processing experience.

First of all, for patients, the most concerned question is whether a certain symptom of is an adverse reaction to immunotherapy ? How serious is as as ? Do I need to stop immunotherapy?

Secondly, for doctors, it is necessary to quickly determine whether the symptoms of the patient are adverse reactions of immunotherapy, as well as the severity of differential diagnosis and adverse reactions, master the use of medications for handling adverse reactions and the evidence of stopping immune drugs, and also know which adverse reactions can be solved by yourself and which ones require the assistance of a specialist to consult.

I hope what I said today will be helpful to everyone.

Part 1

I believe everyone is familiar with the mechanism of the "throttle" and "brake" of immune checkpoint inhibitors. There are very vivid and specific explanations in the popular science of the White Rabbit Moderator. If you haven't learned it, you can browse it and deepen your understanding of tumor immunity. Today we won't talk about the accelerator and brake. I would like to use the balance model to talk to you about the relationship between the treatment of immune checkpoint inhibitors and adverse reactions. There are currently three drugs used in clinical practice: PD-1, PD-L1, and CTLA-4 monoclonal antibody. The adverse reactions related to immune checkpoint inhibitors that we are talking about today are mainly produced by these three drugs.

This is a simple diagram I made. The picture on the left shows the state of the normal immune system of the human body. When our immune system works, it will be restricted by two forces. One power is to suppress the immune system, and the other power is to activate the immune system. Only when the two forces are balanced can the human immune system be normal. can actually be simply understood as: the stronger the human immune system, the better, and it is the most appropriate to be in a state of equilibrium. If immune suppression, then diseases such as tumors and immunodeficiency diseases may occur; if immune activation is excessive, the human immune cell will attack our own organs, producing autoimmune diseases such as rheumatoid arthritis, lupus, myositis, etc. Therefore, our human immune system should neither have immune defects, so that "foreign enemies" and tumors can take advantage of it; nor do we attack our own tissues too strongly, which will lead to autoimmune diseases and create an embarrassing situation of "one's own people beat their own people".

. The immune detection point inhibitor treatment was originally intended to enhance the body's immunity, but overcorrection occurred during the treatment process, resulting in excessive activation of the immune system, causing its own immune cells to attack its own tissues and organs, which led to corresponding adverse reactions.

or above is the mechanism of the treatment and adverse reactions of immune checkpoint inhibitors. To be more common, the adverse reactions produced by immune checkpoint inhibitors are actually caused by excessive immune activation. So what are the manifestations of excessive activation? The possible mechanisms currently studied include: , excessive activity of immune cells in the body; 2, increase in cytokines that promote inflammation, and 3, increase in autoimmune antibodies. may have other more complex immune mechanisms that cause the body's immune system to overactivate, attacking its own normal tissue while killing tumors.

So what if there are related adverse reactions in the treatment of immune checkpoint inhibitors? We need to suppress the human immune system through various immunosuppressants drugs, corrects the over-activated state and readjust the balance. Currently, the most commonly used immunosuppressants in clinical practice include:

• hormones: This is a broad-spectrum immunosuppressant that inhibits the body's cellular and humoral immunity. Commonly used are the oral drug prednisone acetate tablets, and the intravenous ones include marsone. Pay attention to side effects such as hyperglycemia, hypertension, osteoporosis, and ulcers during the medication.
• Cytotoxic drugs: can inhibit the proliferation of T cells. Common drugs include mycophenolic acid esters (the one that is used more frequently is Xiaosi), methotrexate and cyclophosphamide. However, the latter two have relatively large side effects and are generally used in arthritis and kidney damage. Common adverse reactions include myelosuppression and induce infection.
• Calcium phosphatase inhibitor: mainly inhibits the T cell activation factor IL-2, causing T cell function to lose. This type of drug has relatively few side effects, but drug concentration needs to be detected. However, many local hospitals cannot detect drug concentrations, which limits the use of these drugs.
• Biologics: directly inhibits cytokines and integrins, and infliximab inhibits TNF-a. The new drug vetolizumab inhibits integrin receptors and inhibits immune cell activity. Because when intestinal mucosa is inflamed, immune cells are abnormally active and the cytokines secreted increase, resulting in intestinal mucosa inflammation damage. Therefore, if immune-related enteritis is not good, you can first consider combining this type of drug. Another type is antibodies that directly inhibit T cells. Commonly used are anti-thymocyte globulin, which directly inhibits T cells produced by the thymus, and has a strong inhibitory effect. It is generally only used for very difficult to control and relatively dangerous adverse reactions, such as myocarditis .

Generally speaking, most immune-related adverse reactions are very effective through hormone treatment. The more serious adverse reactions of require combined with 1-2 immunosuppressants.

Problem in the use of medication for special populations: Now the threshold for medication for immune checkpoint inhibitors is getting lower and lower, but some hospitals use medication directly without screening special populations before taking medication, which requires us to pay attention.

Autoimmune disease patients:

Above, we talked about the adverse reactions of immune checkpoint inhibitors and the pathogenesis of autoimmune disease. Autoimmune disease is a disease that can affect various organs of the body, such as rheumatoid arthritis, myasthenia gravis , lupus, psoriasis, ulcerative colitis, etc. Using immune checkpoints to treat this type of population may aggravate the condition and even endanger life (such as patients with myasthenia gravis). People with tumors and autoimmune diseases cannot use immune checkpoint inhibitors at all, but they must be closely monitored when taking medication, and try to minimize hormone medication before using immune medication. However, try not to use some more serious autoimmune diseases that may be life-threatening, such as myasthenia gravis.

Bone marrow and organ transplant patients:

This type of patients may not have a good effect on immune checkpoint inhibitors, and at the same time increase the risk of organ rejection.

patients with hepatitis

my country is a major hepatitis B country, and there are many patients with tumors and hepatitis, but they usually do not affect their use of immune checkpoint inhibitors. The liver toxicity is a little higher than that of normal people during the medication process, but most of them can be relieved after treatment. For patients with HBV infection, immune checkpoint inhibitor treatment should be initiated after the HBV-DNA is less than 2000 IU/ml. HBVDNA is not high, but HBsAg (+) and/or HBcAb (+) is also recommended to give antiviral treatment (entecavir or tenofovir ester) before the first use of immune checkpoint inhibitors, and regularly monitor HBV-DNA and HBV surface antigens and antibodies; for people with hepatitis C infection, DAAs or interferon antiviral treatment is not required while treating immune checkpoint inhibitors, but regular monitoring of HCV-DNA levels is still required. Patients who replace immune checkpoint inhibitors with

:

generally does not recommend patients to replace immune checkpoint inhibitor drugs. For example, if PD-1 monoclonal antibody was used before and then CTLA-4 drug, the efficacy will not change much, but the risk of adverse reactions has indeed increased.

study shows that the adverse reaction spectrum and incidence rate of patients younger than 70 years old and older is comparable, but considering that there are many other factors affecting death in elderly patients, CTLA-4 or combination therapy is not recommended.

Immunized patients: Inactivated vaccine can be used during the treatment of

. If influenza vaccine, cervical cancer vaccine, and hepatitis B vaccine can be vaccinated, live vaccine cannot be vaccinated. Before getting the vaccine, check the type of vaccine.

Generally, patients with poor conditions:

ECOG score is greater than 2, and the risk of adverse reactions is greater, use with caution. Pregnant patients are prohibited, and AIDS carriers are also used with caution.

Part 2

Home will tell you some common characteristics of adverse reactions related to immune checkpoint inhibitors:

. The adverse reaction spectrum produced by different immune checkpoint inhibitors is different

CTLA-4—Enteritis, pituitary inflammation, and skin are more common;

PD-1 inhibitor—immune pneumonia , muscle, joint pain, and hypothyroidism are more common.



• . The toxicity spectrum produced by the same immunosuppressant when acting on different tumors is also different

  

  Whether it is a different immune checkpoint inhibitor or a different cancer type, we will find that the most attacks are always those organs. No matter how the situations outside are changing, immune checkpoint inhibitors always have their own organs they love. Let’s review the mechanism of adverse reactions: 1. Overactive immune cells in the body; 2. Increased cytokines that promote inflammation, 3. Increased autoimmune antibodies. So based on these mechanisms, we can actually infer which important organs of the human body are most popular in addition to tumors.

  First of all, it has a lot of immune cells, which is the place where the immune response is most active. Do you know which organs it is?

  As a reminder, they are some open organs that are in close contact with the external environment. Because they have to fight against foreign invasions at any time, their immune response is relatively active.

  pair is our skin and mucous membranes with rich digestive tract and respiratory tract , because the skin and mucous membranes are important barriers to resist foreign microbial infections, and the immune response is very active.

  Therefore, our skin, digestive tract (the lymphatic tissue of the intestine is extremely rich), and lungs are organs that are very susceptible to immune checkpoint inhibitors. Not only immune checkpoint inhibitors, autoimmune diseases, and rheumatisms like to attack these organs the most.

  immune checkpoint inhibitors can lead to an increase in autoimmune antibodies. So where do these antibodies go? They will wander in the blood of the body and will be deposited into various organs in the human body. They also have some organs that they particularly like, such as the endocrine system, muscles and bones, and our powerful liver (a variety of immune cells, and an organ that produces various immunoglobulins) and kidney (an organ that is favorite for the deposition of antigen and antibody complexes).

  also has some special habits, which gather in the heart, blood system, nervous system, and eyes, resulting in some relatively rare adverse reactions.

  I don’t know this explanation. Can you remember the organs that are most likely to have adverse reactions related to immune checkpoint inhibitors? Based on the functions of each organ, we can quickly infer the symptoms of related adverse reactions and tell you these. hopes that our patients and doctors can understand and remember more systematically and comprehensively what adverse reactions can be produced by immune checkpoint inhibitors. It is far from enough to know only a few common adverse reactions reported in clinical experiments.

  , Let me give you an example. We have a patient with lung adenocarcinoma in other places. After two cycles of cisplatin + pemetrexed combined with K drug (Pembrolizumab), they suddenly experienced ptosis of both eyelids and restricted neck movement. The creatine kinase has soared to more than 3,000. Because they could not come to Beijing during the epidemic, they called us for consultation. We considered that immune-related muscle injuries may be combined with myasthenia gravis. If this adverse reaction continues to develop, it will be very serious. Once the respiratory muscles are involved, life will be in danger at any time.We quickly asked them to hit the local hospital intravenous Arosaurus. Perhaps because of the epidemic, the hospital may also think that this adverse reaction is difficult, and no local hospital is willing to accept it. There was no choice but to let him take a lot of hormones orally. A week later, the patient's symptoms quickly alleviated.

  We also know that among the immune adverse reactions related to lung cancer, pneumonia and hypothyroidism are more common, and it is easier to find them, but some rare adverse reactions occur unexpectedly, and are unpredictable, refreshing our understanding every day. Because the treatment of immune checkpoint inhibitors has just been approved in China, and the threshold for use of immune checkpoint inhibitors is getting lower and lower, many doctors have insufficient understanding and experience in handling adverse reactions. Therefore, for patients and doctors, it is very important to promptly discover these less common adverse reactions that may be life-threatening. Later, I will divide the system into organs and tell you about the adverse reactions that may occur in turn to deepen your impression.

. Different adverse reactions occur at different times. Most of the adverse reactions are reversible



immune checkpoint inhibitor adverse reactions can occur at any time at the beginning, during and after the end of the treatment, but most of them are within 3 months of the beginning of the immune checkpoint inhibitor treatment, so you cannot relax your vigilance against the detection and evaluation of adverse reactions at any time.

4. The incidence of adverse reactions in real-world cases is much higher than that reported by clinical studies and literature

Part 3

. Let me tell you about the symptoms and treatment methods of possible adverse reactions in each system in the order of high to low incidence.

Skin toxicity

First, let’s take a look at the skin-related adverse reactions with the highest incidence. Skin-related adverse reactions generally occur earlier, and most of them are delayed in the first few days or weeks of treatment. Most reactions are relatively mild, and serious adverse reactions are very rare.

The main clinical manifestations of skin-related adverse reactions include maculopapular rash, itching, and blisters.





mpause rash is the most common skin adverse reaction, which may be accompanied by itching. It is classified according to the range and size of the rash. If the rash area is less than 10%, it is set as level 1. There is no need to stop the immune checkpoint inhibitor. can use a bit of emollient cream, apply hormone ointment locally or oral antihistamine drugs, and Kelitin and Kelitin drugs. area 10%-30% is set as Level 2. There is a little difference between the CSCO guidelines and ESMO guidelines. The CSCO guidelines recommend suspending treatment, while the ESMO guidelines recommend that if the rash area is 10-30% but the symptoms are mild, the immune checkpoint inhibitor treatment can be continued. html-level 42 treatment generally requires topical hormones, oral hormones, and antihistamine drugs to treat . The area is greater than 30% to be set at level 3-4. At this time, the treatment of immune checkpoint inhibitors needs to be stopped. We generally recommend that patients go to the dermatology clinic directly. The dermatology department will combine several antihistamine drugs for treatment based on topical and oral hormones, and it is not well controlled, and some other immunosuppressants are added. Adverse reactions of

immunotherapy also need to be classified, and the severity of these adverse reactions is determined by grading clinical manifestations and indicators. For example, in skin-related adverse reactions, the percentage of rashes to the body surface area is usually evaluated. So how to evaluate this? We generally judge based on the burn area assessment method. Let me tell you two evaluation methods. The first method is to measure our own palms, and the area of ​​one palm accounts for about 1% of the total body surface area. Suitable for small-area rash measurement.



So how should we measure large-scale rashes? It is also a 9-point method for burn area. The head, face and neck account for 3%, both hands, forearms and upper arms account for 5, 6, and 7 respectively, and the front and back of the trunk account for 13%. Based on this, the rash area is calculated.





The following tests everyone, how many levels can this patient’s skin adverse reactions constitute? This patient has both the face and the entire front chest. Let's calculate the area of ​​this rash.

+3+3+13+13=35%. More than 30%, it is a grade 3 skin adverse reaction.

HTM1 Our department has used immune checkpoint inhibitors for about 7 years, and we have not encountered a case of adverse skin reactions of level 3 or above. Although there are many adverse skin reactions, don’t be too anxious, because it is rare to stop treatment with very serious adverse skin reactions.



The second symptom - the itching sensation assessment is subjective. Generally speaking, if you have mild itching, you can use hormone ointments and oral antihistamine drugs. But here I remind you that no matter how many adverse reactions, we should consult the dermatology clinic to buy medicines to avoid using the wrong medicine. If very strong and extensive itching occurs and the skin is scratched, consider suspending the immune checkpoint inhibitor first, using hormone ointments, and returning to level 1 after oral antihistamine treatment. If the itching symptoms are very strong and severely affect your life, the treatment of immune checkpoint inhibitors will be suspended first. At this time, you must ask the dermatologist to help solve the problem. The third symptom of



is also a relatively serious adverse skin reaction. Bullusion and peeling appear on the skin, similar to the manifestations of these two pictures. If this is not processed in time, it will be combined with infection and endanger life in severe cases. When the third type of skin damage occurs, don’t make things difficult for the oncologist. Go to the dermatologist for treatment as soon as possible. This will definitely require hormone impact and topical medications, and skin care should be strengthened to prevent symptomatic treatment of infection. Generally speaking, for patients with maculopapular rash or itching, as long as the symptoms can recover to level ≤1, they can consider using immune checkpoint inhibitors again. But a third of this serious life-threatening vesicular disease, epidermal necrolysis and DRESS, considering permanent discontinuation of immune checkpoint inhibitors. This requires our doctors and patients to discover and intervene in a timely manner.



Now clinical studies have found that skin-related adverse reactions often indicate that PD-1 treatment is effective. Our department has also experienced 2-3 patients with grade 2 rash, and the treatment effect is very good. One patient has direct CR, which means clinically cured.

But please note that some patients are still very good at taking medication now. They see that the treatment effect is good and there are adverse skin reactions, but they are afraid that the use of hormones will affect the effect of immunotherapy, so they allow the adverse reactions to develop freely, and irreversible consequences may occur. Everyone must detect and deal with them early.

also has a special skin adverse reaction - skin hemangioma. Most of this adverse reaction is the use of Hengrui's carrilizumab. Most skin hemangiomas are single-shot, mainly for observation and prevention of infection, without hormone treatment, patients who use Hengrui PD-1 antibody pay more attention.

gastrointestinal toxicity

After talking about the skin part, let’s talk about adverse reactions to the digestive tract and respiratory tract that are vulnerable to attack and are in close contact with the outside world.



The main manifestation of gastrointestinal adverse reactions is diarrhea/colitis, which is a very common adverse reaction. The incidence of gastrointestinal adverse reactions of CTLA-4 inhibitors is much higher than that of PD-1/PD-L1 inhibitors, and occurs at any time during treatment, while the adverse reactions of PD-1/PD-L1 inhibitors generally occur 3 months after medication.

Most patients have lesions in the lower sigmoid colon and rectum, and it is rare to involve the stomach and small intestine. Colonoscopy is mostly manifested as mucosal erythema, erosion, and ulcer formation. It is mainly manifested as diarrhea, and may also have symptoms such as abdominal pain, bloody stools, mucus, and fever. A small number of patients may have oral ulcers, anal lesions (anal fistula, abscess, anal fissure), as well as joint pain, endocrine disorders, skin lesions and other parenteral symptoms.

If the number of diarrhea is less than 4 times per day and there are no symptoms such as abdominal pain and bloody stool, it is a mild grade 1 adverse reaction , because many patients are combined with chemotherapy and immunotherapy. Chemotherapy itself can also cause diarrhea, and infection can also cause diarrhea during the treatment process. When the patient has symptoms of diarrhea, we will first exclude the infection factors and observe the symptoms and stop diarrhea. Most symptomatic support can also improve, and there is no need to stop the treatment of immune checkpoint inhibitors.

If diarrhea is 4-6 times per day, accompanied by symptoms such as abdominal pain, bloody stool, and mucus, it is a grade 2 adverse reaction.

If the number of diarrhea is greater than 7 times per day, accompanied by severe abdominal pain, bloody stool, and mucus, it is a grade 3 adverse reaction. When the patient experiences symptoms of life-threatening symptoms such as dehydration, shock, and intestinal perforation, it is a final grade 4 adverse reaction.

For patients with immunotherapy-related enteritis, our experience in handling is that first excludes the infectious cause and supports symptomatic support for 1-2 days. If it does not improve, empirical treatment with hormones will be started. Level 2 enteritis will be suspended for immune checkpoint inhibitor treatment, and intravenous hormone 1 mg/kg/d will be used for 2-3 days. If the symptoms do not relieve, increase to 2 mg/kg/d (if there is a need to clarify the cause, then colonoscopic biopsy will be performed). Grade 3-4, intravenous hormone 2mg/kg/d, observation for 2-3 days is not effective, combined with other immunosuppressants, infliximab or vetolizumab.

Most immune-related enteritis single-agent hormone treatments can be well controlled. At present, we use immune checkpoint inhibitors in our department and gastroenterology to have enteritis basically occur at level 2 or below, and level 3 is rare, and it is very effective for single-agent hormones. There are no cases of using other immunosuppressants yet.

verified: if level 1 adverse reaction occurs, continue to treat immune checkpoint inhibitors, first suspend the treatment of immune checkpoint inhibitors in grade 2-3 adverse reactions, consider re-immune checkpoint inhibitors after the symptoms are relieved, and the drug should be permanently discontinued. The problem of despair of enteritis hormone: oral hormone 0.5mg-1mg/kg/d, generally maximum amount 60mg, and intravenous doses are generally 1-2mg/kg/d. According to the patient's symptoms, the dose will be reduced by 3-7 days after remission, and it will be reduced by about 10% per week. The treatment time is at least greater than 4 weeks, and the suspension will be completely reduced by 6-8 weeks. Patients taking oral medication at home must pay attention that should not stop suddenly when the symptoms are relieved. They should gradually reduce the dose and stop the medication slowly.

Pulmonary toxicity

Immune-related pneumonia is a life-threatening and serious adverse reaction. It usually occurs 2-3 months after treatment, and it is more active in handling than enteritis. All ovarian cancer patients are women, and they rarely have a history of smoking. They have fewer underlying lung diseases (COPD, pulmonary fibrosis) than those of lung cancer patients. Therefore, the incidence of immune-related pneumonia is not high, but it does not mean that there is no. Since immune-related pneumonia is coming and progressing very quickly, patients and doctors should still diagnose quickly and stop the medication in time to avoid missing the best treatment opportunity.



lung cancer patients reported less than 5%, but in fact the incidence of pneumonia is much higher than this rate, and it has been reported that it can reach 20-40%. The clinical symptoms of immune-related pneumonia mainly include dyspnea (53%), decreased activity tolerance, cough (35%), fever (12%) or chest pain (7%), but about 1/3 of the patients have no symptoms and only imaging abnormalities. The main basis for diagnosis is chest CT, which is more common ground glass nodules or patch nodules infiltration, which needs to be differentiated from inflammation.

recommends that patients take a chest CT before using immune checkpoint inhibitors. As a baseline assessment, lung cancer is routinely used for CT to evaluate the primary lesions. Therefore, it is recommended that ovarian cancer patients undergo chest CT examination once every 3-6 months when using immune drugs. If symptoms such as chest tightness, shortness of breath, and cough occur, do chest CT at any time.

judges mild, moderate and severe according to the patient's symptoms and CT. Our experience is that once a patient has suspicious lesions on the lungs, mild patients will first observe temporarily, check the infectious indicators, first treat empirical antibiotics, and then take CT for evaluation for 3-4 weeks. Some patients directly show symptoms of shortness of breath and cough, and the CT lesion range is greater than 25%. This is a Grade 2. Patients with Level 2 will directly discontinue immune checkpoint inhibitor drugs, and empiric antibiotic treatment combined with hormone treatment. Some patients found that they were already level 3 (with clinical symptoms + chest lesions greater than 50%), while others had poor control progress in level 2 and developed to level 3-4. The treatment was still difficult. Start empirical antibiotic treatment with high-dose hormone impact for 48 hours as soon as possible. If there is no improvement, combined with Gen C immunoglobulin or other immunosuppressant treatment.Most patients with immune-related pneumonia are effective against hormones, but 15%-30% of patients do not respond to hormones, resulting in poor prognosis in these patients. Our department has encountered several cases, one of which died of immune-related pneumonia. Therefore, we must be more proactive in handling pneumonia.

hormone reduction method for patients with pneumonia. After the initial dose (1-2 mg/kg/d) hormone onset (48 h-72 h), continue to maintain the original dose until 7 d-14 d, and then start to gradually reduce the dose by 20% every two weeks. The overall course of treatment should be controlled for at least 4 weeks, and the suspension should be reduced for 6-8 weeks. After the treatment of

immune-related pneumonia, challenge the problem of immune checkpoint inhibitor again: If the patient has achieved complete remission of the early immune checkpoint inhibitor and the treatment cycle is almost enough, it is recommended not to use the medicine and observe it; if the early disease progresses, it is definitely no longer considered receiving immune checkpoint inhibitor treatment; if the early immune checkpoint inhibitor has achieved partial remission or the disease is stable, but the treatment cycle is insufficient, you can consider challenging again.

Immune-related pneumonia: For those with sensitive hormone therapy, they should consider challenging again; for those with sensitive hormone therapy and good recovery, they should consider challenging again. If we challenge again, we generally choose the original medicine and try not to change the medicine.

endocrine system toxicity

below talk about organs that immune checkpoint inhibitors like to attack. First of all, the first one that is most vulnerable to attack is the human body's endocrine system. You may have a sense of the skin, intestines, and lungs, and it is difficult to have an intuitive impression of the endocrine system. So let’s briefly understand the endocrine family.



endocrine system is the organ that secretes hormones (hormones). This picture shows me the main organs of the endocrine system. There are hypothalamus, pituitary , thyroid , adrenal , gonads, thymus, and pancreatic that secretes insulin . Moreover, the endocrine system is a highly hierarchical system. Hormones are the communication soldiers for ventilating and information. Any communication soldiers assigned to work below must obey the unified arrangements of superiors.



endocrine system also has a particularly important hierarchical organization, which is displayed to us by this picture. The hypothalamus is the highest commander, commanding the grassroots commander - the pituitary gland. Only after the pituitary gland receives commands from its superiors will secrete hormones and issue tasks to the target organs below. Immune checkpoint inhibitors are most likely to attack the executive's thyroid gland, or the adrenal glands and gonads. Some directly destroy the executive's superior-pituitary gland. The most common immune-related endocrine toxic reactions in the endocrine system are: abnormal thyroid function (demonic as hypothyroidism and hyperthyroidism) and pituitary inflammation (impaired commander will lead to hypopituitary function, resulting in central hypothyroidism, central hypoadrenal, and central hypogonadism). Other immune-related endocrine diseases are relatively rare, such as primary hypoadrenal, type I diabetes, idiopathic postprandial hypoglycemia, etc.

Before starting the treatment of immune checkpoint inhibitor, it is recommended that patients improve thyroidism, blood sugar (fasting glucose, glycated hemoglobin), adrenal function (8am corticotropin ACTH and cortisol, if necessary, add ACTH and cortisol and cortisol at 4pm and 12am to understand hormone rhythm changes).

Let me first talk about the most common target organ: the thyroid gland.



The probability of abnormal thyroid function is about 6-20%, including hypothyroidism and hyperthyroidism. It usually occurs 1 month after treatment.



If symptoms such as indifference, fatigue, fatness, constipation, and drowsiness appear during the treatment process, first consider the possibility of hypothyroidism. The A-technology test is manifested as an increase in TSH and a decrease in FT4. Some patients with have no symptoms and are abnormal TSH and FT4 found during regular re-examination. Then the TSH is between 4-10, and it can be observed that if the TSH is greater than 10, thyroxine replacement treatment can be started. For hypothyroidism with clinical symptoms, thyroxine replacement therapy is recommended.

It should be noted that patients with simple hypothyroidism do not need to stop the immune checkpoint inhibitor treatment. They can test work thyroxine replacement therapy, and do not need glucocorticoid treatment. However, here we need to distinguish between central hypothyroidism (hypothyroidism caused by pituitary injury) caused by pituitary inflammation.



When eating and drinking more, you don’t gain weight, irritability and palpitations, you should consider that hyperthyroidism may occur. The thyroid dysfunction is elevated FT4 and decreased TSH. Thyroid stimulating receptor antibodies (TRAbs) and thyroid peroxidase (TPO) may also have abnormalities. Usually, immune-related hyperthyroidism is self-limiting (can be relieved by itself), and may even be reduced in the later stage. Therefore, the occurrence of hyperthyroidism is mainly based on observation and does not require drug treatment. For patients with palpitations and palpitations, beta blockers (betaloke and other drugs) can be given to control the symptoms; check the thyroid dysfunction every 3-4 weeks; once the thyroid hypothyroidism occurs, thyroid hormone replacement treatment can be performed. When hyperthyroidism occurs, we generally do not stop taking the medicine unless there is a relatively serious hyperthyroidism that threatens life.

Summary: Hypothyroidism and hyperthyroidism do not require the discontinuation of immune checkpoint inhibitor treatment, nor does glucocorticoid treatment be required. Test work thyroid in regular intervals. Patients with hypothyroidism should pay attention to excluding central hypothyroidism and thyroxine replacement therapy.

The second lower target gland is the adrenal gland. The incidence of adverse reactions in is very low, but we at least understand what symptoms will occur in this adverse reaction. The adrenal glands are a very important endocrine organ. The adrenal glands are like an egg. The egg white is equivalent to the adrenal cortex, secreting familiar glucocorticoids, as well as aldosterone (sodium-saving potassium, blood pressure-raising hormone) and sex hormones. The egg yolk is equivalent to the adrenal medulla and secreting epinephrine (pharyngeal hormone). If immune checkpoint inhibitors cause adrenal insufficiency, these hormones will be secreted, especially glucocorticoids and aldosterone. What are the symptoms?



Think about it, we generally use glucocorticoid to treat anorexia and diarrhea, because it can promote the secretion of gastric acid and pepsin, enhance appetite, and promote digestion. At the same time, due to the impact on protein metabolism, gastric mucus secretion is reduced, which can induce or aggravate ulcers and cause some side effects. So if you lack it, you will experience fatigue, anorexia, nausea and diarrhea.

glucocorticoid reduction will weaken the negative feedback inhibition of melanocyte hormones and ACTH, causing excessive secretion of melanocyte hormones and adrenocorticotropic hormones, which can darken the skin and pigmentation in the skin.

Decreased glucocorticoids can lead to hypoglycemia. Glucocorticoids are an important insulin antagonist hormone in the body. Increased glucocorticoids can increase insulin resistance and affect skeletal muscles' uptake and utilization of glucose by adipocytes. In addition, it can directly inhibit the function of pancreatic islet B cells, reduce insulin secretion, and ultimately increase blood sugar.

Aldosterone and epinephrine secretion will cause orthostatic hypotension, dizziness, fainting, and even shock.

If these symptoms occur, you must think of evaluating adrenal function (ACTH and cortisol hormone). Think about it, this organ has affected the production of so many important hormones, so you should be more cautious. After diagnosis, the treatment of immune checkpoint inhibitors will be suspended first. Endocrinology department is required to consult and provide hormone replacement therapy. The third adverse reaction that is more prone to occur is that the pituitary gland of the intermediate commander of this level of tissue is damaged. is more common in patients treated with CTLA-4 antibody. It usually occurs 8-9 weeks after treatment and 10-24 weeks after treatment.



We know that the pituitary gland is the commander of the adrenal glands, thyroid glands, and gonads. If the pituitary glands are damaged, the downstream target glands will not function normally, so the symptoms will be more severe. Therefore, hypothyroidism caused by pituitary damage is called central hypothyroidism (also central hypoadrenal glands, etc.). If not promptly discovered or intervened as soon as possible, it may lead to serious fatal consequences.Moreover, the clinical symptoms are not very typical. Many times, it may be misdiagnosed. Some patients in some places have fever and headaches of unknown causes after using immune drugs. They are very atypical symptoms. They went to multiple hospitals but have not been diagnosed. Finally, after a thorough investigation, they found out the problem of pituitary inflammation. This patient almost died of this complication. Fortunately, they were discovered in time.

If there is unexplained persistent headache or visual impairment, fatigue, and fever, improve hormone protactic detection, target gland function and pituitary MRI diagnosis as soon as possible. At the same time, the treatment of immune checkpoint inhibitors should be suspended, and hormone shock treatment and hormone replacement treatment should be used. The adverse reactions in the endocrine system, except for pituitary inflammation that requires glucocorticoid treatment, other adverse reactions are hormone replacement treatment and symptomatic treatment.

Let’s talk about another important gland in the endocrine system - pancreatic islet . Its function is to secrete insulin and regulate blood sugar. Everyone should know that the blood sugar fluctuates during the treatment of tumor patients because they use glucocorticoids. Generally, after stopping the treatment, the blood sugar will recover. If it continues, it can also be restored by giving some hypoglycemic drugs.



Maybe every time you treat, everyone will be careless, thinking that this is the increase in blood sugar caused by hormones, and it will be cured in a few days. Therefore, blood sugar testing will be ignored. In fact, we found that when chemotherapy and immunotherapy are combined, some patients have higher blood sugar levels than when chemotherapy is pure, and it is difficult to control. The possible reason is the damage to the pancreatic islets by immune deposits. In mild cases, we cause abnormal insulin secretion and type II diabetes. In severe cases, it directly leads to a complete loss of the entire pancreatic islet function. If insulin is completely secreted, it will become type I diabetes.

We have a patient who has no diabetes and his blood sugar has always been normal. After 18 cycles of O-drug use, he suddenly had increased fasting blood sugar, polyuria, thirst, weight loss, nausea, and vomiting. He went to the hospital for examination and had complications of ketoacidosis. He checked C peptide and insulin antibodies (insulin function examination item), and found that insulin secretion was almost zero. The endocrinology department diagnosed with type I diabetes and was accompanied by ketoacidosis. This type of patient will have to permanently stop the medication in the future. Although immune checkpoint inhibitors cause type I diabetes, type I diabetes is prone to complications, and the treatment is different from type II diabetes and steroid diabetes. Therefore, if we detect the continued increase in fasting blood sugar or sudden increase, and the effect of hypoglycemic drugs and insulin is not good, we must detect the urine ketone body and insulin function at any time. The cost of blood sugar testing is not high and it is very easy to operate. It is recommended that patients undergo blood sugar testing more frequently during medication.

liver toxicity

immune checkpoint inhibitor-related liver adverse reactions most often occur 8 to 12 weeks after the first medication. Because during the treatment period, we check at least blood routine and liver and kidney function in each treatment cycle, it is easier to find liver adverse reactions. The adverse reactions in the liver are mainly manifested in increased aminotransferase, which can also be accompanied by increased bilirubin. Some people may have very inspecific symptoms, such as fever, decreased appetite, and anorexia, which are common symptoms that cancer patients have. There are also some slightly specific symptoms. If the skin becomes yellow and the urine becomes darker, then go to the hospital to check the liver function and whether liver damage occurs after treatment.



transaminase increase occurred during the treatment process. First, we must rule out whether the patient has a history of hepatitis, fatty liver, alcohol liver, and whether he has used liver injury drugs (because there will also be liver damage during chemotherapy). Whether there was autoimmune hepatitis in the past is also important. We must evaluate whether liver metastasis occurs. Only after these factors are excluded can we consider immune-related liver injury.

is classified according to the aminotransferase value. If the aminotransferase value is less than 3 times the normal value, it is determined to be mild. We generally keep immunizing drugs, treat the liver symptomatically and closely observe changes in liver function.If the normal aminotransferase value is 3-5 times, it is determined to be moderate. It is necessary to pause the treatment of immune checkpoint inhibitors, protect the liver, and closely observe changes in liver function. You can also consider using hormones. If the liver function continues to deteriorate, hormone treatment is needed as soon as possible. The aminotransferase value is 5-20 times higher than the normal value and is determined to be severe. The immune checkpoint inhibitor treatment should be permanently discontinued, liver protection symptomatic treatment should be combined with hormones, and liver function should be closely monitored. If the effect is not good, you can combine it with another immunosuppressant, such as tacrolimus or Xiaosi. There is another situation where if the aminotransferase increase is greater than level 1, the bilirubin increase is greater than 1.5 times, it will also be severely damaged. There is a quantitative indicator for liver injury, so grading is relatively easy. So let me tell you about a case and give you a diagnosis and treatment plan.

A 56-year-old male patient with lung squamous cell carcinoma, no history of viral hepatitis,

GP+Keytruda chemotherapy for 4 cycles.

-10The liver function is normal.

-12 Liver function: ALT 470 IU/L (normal value 0-50), AST 690 IU/L (normal value 0-40) Direct bilirubin 8umol/L (normal value 0-6) Total bilirubin 19.9 umol/L (normal value 1.7-20)
-13 Liver function: ALT 415 IU/L (normal value 0-50), AST 675 IU/L (normal value 0-40) Direct bilirubin 8umol/L (normal value 0-6) Total bilirubin 19.9 umol/L (normal value 1.7-20)

Abdominal enhancement CT prompts no obvious placeholding.

excludes viral hepatitis and liver metastasis, and does not consider liver damage caused by chemotherapy, because the increase in transaminase caused by chemotherapy generally does not increase so rapidly. So we diagnosed him with immune-related liver injury. What level of damage do you think this should be considered?

pair, which is a grade 3 liver injury. So how should third-level liver injury be treated? In addition to symptomatic liver protection treatment, the most important treatment is hormone therapy. This patient weighs 75kg, and according to the tertiary hormone treatment dose, it should be 1-2mg/kg/d.

-13 initial dose was given 80mg/day A strong dragon impact treatment, and the liver function was checked the next day.

-16 Liver function: ALT 263 IU/L (normal value 0-50), AST 175 IU/L (normal value 0-40) Direct bilirubin 8umol/L (normal value 0-6) Total bilirubin 17 umol/L (normal value 1.7-20)
-23 Liver function: ALT 99 IU/L (normal value 0-50), AST 47 IU/L (normal value 0-40) Direct bilirubin 6umol/L (normal value 0-6) Total bilirubin 8.3umol/L (Normal value 1.7-20)

-24 (Second week) Aphrogenic dragon began to reduce the dose to 60mg/day (10% reduction per week)

-4 Liver function: ALT 60 U/L (Normal value 0-50), AST 46 IU/L (Normal value 0-40) Direct bilirubin 4.3umol/L (Normal value 0-6) Total bilirubin 5.2umol/L (Normal value 1.7-20)

-4 (Fourth week) Intravenously changed to oral, prednisolone acetate 50mg/day, oral, (5 mg of prednisone acetate = 4 mg of methylangrolu)

-9 (Fifth week) Prednisolone acetate 40 mg/day, orally taken

-9 (Sixth week) Prednisolone acetate 30 mg/day, orally taken

-9 (Seventh week) Prednisolone acetate 20 mg/day, orally taken

-9 (Eighth week) Prednisolone acetate 10 mg/day, orally taken for one week, stop the medication. During the treatment period, patients' blood sugar increased significantly. Insulin lowering glucose treatment is given, calcium supplements and vitamin D are needed to prevent and treat osteoporosis. Proton pump inhibitors (omeprazole) prevent gastrointestinal reactions.

This is the entire process from diagnosis to treatment for patients with immune-related liver injury. Fortunately, he is hormone-sensitive and quickly controlled after treatment with hormones, but unfortunately, he can no longer be treated with immune checkpoint inhibitors in the future.

Although permanent immune checkpoint inhibitors for level 3 damage are still controversial, most of them are not recommended to use them again, unless the person is sensitive to hormones, the liver injury will reach level 1, and the treatment is effective, but the treatment cycle is not enough and there is a possibility of restart, but the liver function must be closely monitored.

If there is liver metastasis, the aminotransferase itself is high. Generally, the liver function within grade 2 liver toxicity can be treated with immune checkpoint inhibitors; if there is liver damage related to immune checkpoint inhibitors, the increase in ALT/AST exceeds 50% of the baseline and lasts for more than 1 week. The treatment of immune checkpoint inhibitors must be permanently stopped.

Musculoskeletal toxicity

Here are some of the higher incidence of joint and muscle adverse reactions. Most tumor patients have more or less musculoskeletal symptoms, so there are many clinical trials of muscle and bone adverse reactions, which may not be true adverse reactions.





The real immune-related adverse reactions occur between 2 months and 24 months after treatment. The main manifestations are the same as rheumatoid arthritis. The early symptoms are stiffness in the hands and feet when you wake up in the morning, which can last for 30-60 minutes, accompanied by pain and swelling; if it is more serious, joint deformities will occur.



In mild cases, nonsteroidal anti-inflammatory drugs ( ibuprofen ) or small doses of hormones can be relieved, while in severe cases, other immunosuppressive agents may be needed for treatment. If there are more typical joint pain symptoms, we generally recommend that they go to the rheumatology department for further treatment, evaluate the severity, and work with the oncologist to decide on the next treatment plan. Generally speaking, the prognosis of joint injury is better, and immune checkpoint inhibitors are generally not stopped.

Myositis caused by immune checkpoint inhibitors is rare compared to arthritis. It usually occurs in the first two months of treatment of immune checkpoint inhibitors, and the disease occurs more acute. Patients often have myalgia, muscle weakness, and may have elevated creatine myozyme. In severe cases, it may involve the respiratory muscle or myocardial life-threatening. A few patients with myositis (including myocarditis) caused by immune checkpoint inhibitors may also have myasthenia gravis. Do you still remember the previous patient who had adverse reactions during the epidemic? The eyelids are drooping, the neck cannot twist, and more than 3,000 creatine kinase. We consider that this patient has myositis and myasthenia gravis. This situation must be handled positively.

During the use of immune checkpoint inhibitors, be sure to pay attention to changes in creatine kinase and systemic muscle pain assessment. If the patient only shows myalgia, symptomatic pain relief treatment can be performed, immunotherapy can be continued, and myozyme levels can be closely monitored. If the myoenzyme shows mild to moderate elevation, but the patient has no symptoms, you can continue to observe or pause the immunotherapy first. For patients with moderate to severe myositis, glucocorticoid treatment is recommended.

renal toxicity

previously reported that the incidence of renal injury is not very high. Recent studies have found that the incidence of adverse renal reactions is 9.9%-29%, and the incidence is actually not low. Because the kidneys are organs that immune complexes like to deposit. Acute renal injury generally occurs several weeks to several months after treatment of immune checkpoint inhibitors, and tubular interstitial nephritis is the most common renal adverse reaction. The main manifestation of kidney damage is the increase in creatinine, because renal function is more frequently detected, and intervention and treatment rarely begins after it reaches level 3 or above.



is more complex and diverse because the factors that cause kidney damage are more complex and diverse. First of all, we must ask in detail about the medical history, whether we have drunk too little water recently, whether we have prerenal injuries such as diarrhea and infection, whether we have taken drugs such as ibuprofen, Fenbid NSAIDs and proton pump inhibitors such as omeprazole, and if the creatinine is slightly increased, which is less than twice the normal value, we generally keep immunizing checkpoint inhibitors, first hydrate treatment, find the cause, and closely detect renal function. If the progressive elevation is still progressive, you need to ask the nephrology department to evaluate the degree of kidney damage. Is it necessary to make a clear diagnosis of kidney penetration? When to stop the medication, and when to need immunosuppressant intervention and treatment are key issues.

When nephrologists and oncologists consult with this kidney injury together, nephrologists are more inclined to give in to tumor treatment to protect the kidney, because some organs in the human body, such as the thyroid and kidneys, have no function, and alternative treatment and dialysis treatment can often maintain the patient's life for a long time. However, the oncologist still hopes that nephrologists can protect their kidneys. If they enter the dialysis state, further tumor treatment will be more difficult. Therefore, kidney injury should be based on the treatment effect of the patient's immune checkpoint inhibitor, and the consultation opinions of nephrology and oncology should be comprehensively considered in various aspects.

Card toxicity

Home to tell you a few rare but very serious adverse reactions.





Cardiovascular adverse reactions . Although the probability of heart damage reported in clinical trials is not high, the mortality rate is as high as 40-50%. We have also seen several cases in our clinical work. The tumor itself, chemotherapy, and immunotherapy will cause myocardial damage and cause symptoms of heart damage. However, during the process, we tend to classify it as immune-related adverse reactions, and the treatment will be very positive. The reported adverse reactions include cardiomyopathy (mainly myocarditis), as well as pericardial effusion, arrhythmia, acute coronary syndrome and valvular lesions. The occurrence time is 15-30 days after the first medication. If the development is very acute or explosive, the patient has clinical symptoms such as chest tightness, chest pain, dyspnea while moving, and lower limb edema, and it will rapidly worsen within a few days or 1-2 weeks, and even cardiogenic shock or cardiac arrest. The cardiologist described that when I was first used, I didn’t have a deep understanding of the adverse reactions. Several patients with heart damage went to the cardiology department for treatment. At that time, they did not understand that this was an immune-related myocardial injury, so they treated it according to general myocarditis, and the prognosis of the patient was very poor. Later, they gradually gained treatment experience. They usually ask the patient if he has a history of immunotherapy. After a series of examinations, they need to stop the treatment of immune checkpoint inhibitors immediately, and give 1 g of impact treatment of methyl Qianglong as soon as possible, and a very large dose of hormones, which lasts for 3-5 days until the condition begins to improve and then decreases. If there is no sign of remission within 24 hours, human immunoglobulin, anti-human thymus immunoglobulin (an inhibitor with very strong inhibitory effect) or infliximab can be added.

high-risk groups may need to pay special attention. 1. Patients who use immune checkpoint inhibitor drugs in combination with or without other cardiotoxic drugs (such as anthracycline doxorubicin); 2. When there are other system-related toxicities of immune checkpoint inhibitor drugs, especially skeletal muscle and nervous system lesions, pay special attention to whether they have cardiac side effects. 3. Patients with previous autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis) 4. Patients with basic heart diseases (such as coronary heart disease, heart failure, myocarditis, and a history of heart failure after chemotherapy) should also pay special attention.

Pancreatic toxicity

Pancreatic injury is also relatively small. The pancreas includes the endocrine gland and exocrine gland. The pancreas islets that secrete insulin as mentioned above belong to the endocrine gland of the pancreas and the exocrine gland of the pancreas, which specializes in secreting amylase and lipase . In the early stages of using immunosuppressants, many people have mild increases in amylase and lipase, but they can quickly return to normal. Some patients only have an increase in amylase and lipase and have no symptoms. They can continue to immunotherapy, check the cause of the increase, whether there is any metastasis, etc., and closely monitor the changes in amylase and lipase. If there are symptoms of increased amylase and lipase and symptoms of abdominal pain, nausea, vomiting, and increased blood sugar, you must be alert, and pancreatitis may occur.





We have treated a patient with immunoassociated pancreatitis. This patient mainly showed hyperglycemia, with a maximum of 33mmol/L, acidosis, increased amylase and lipase. Considering that the endocrine and exocrine of the pancreas are damaged at the same time, hormone treatment was given after the drug was stopped. The symptoms alleviated after one month. The patient is only 31 years old and has had a good effect after two cycles of immunotherapy. The patient is reluctant to give up and strongly requests to continue using it. However, after another cycle, the symptoms of acute pancreatitis appeared again. This time the symptoms were worse than the last time. The pancreatic duct was blocked, and finally the stent was placed in the intervention to drain the patient's symptoms were relieved. There is no special point in the treatment of immune-related pancreatitis, and timely detection and intervention are required.

Eye toxicity

The incidence of eye adverse reactions is relatively low. If the patient has no eye disease in the past, the symptoms of blurred vision, floaters, flashes, color vision changes, red eyelashes, photophobia, distorted vision, visual field changes, blind spots, soft eyeballs or eye movement pain, eyelid edema or prominent or double vision caused by the first use of immune checkpoint inhibitors, beware of eye adverse reactions.Go to the ophthalmology department for consultation in time and intervene and treat early. Uveitis and scleritis are generally easy to recover in early treatment, but over time, it is difficult to treat, and there may be a risk of blindness.





Neurological toxicity

Immune-related adverse reactions Common neurological reactions include myasthenia gravis, Guillin-Barre syndrome, peripheral neuropathy, meningitis, encephalitis, and myelitis. However, the incidence is relatively low. Most of them are non-specific symptoms of grades 1 to 2, and the incidence of grades 3 to 4 and above is less than 1%. Generally, it occurs 6 weeks after treatment. The symptoms are not specific. Therefore, it is recommended to diagnose adverse reactions of immune checkpoint inhibitors to avoid tumor progression, central nervous system metastasis, infection, diabetic neuropathy, vitamin B12 deficiency, cerebrovascular diseases such as cerebral hemorrhage, cerebral infarction, etc. Differential recommendations are given to consult the neurology as soon as possible.









Let’s briefly understand the symptoms that occur after neurological damage. When such symptoms occur, patients and doctors should be alert to adverse reactions. Myasthenia gravis. I have repeated them three times. I wonder if you have any symptoms of this disease. It is mainly weak in muscles throughout the body. The first manifestation is sagging eyelids, unable to open your eyes, double shadows when watching things, choking and coughing when drinking water, raising your arms, combing your hair, difficulty turning your head, and weakness in your body after moving. It is relatively moderate at night and light in the morning. In severe cases, it will affect the respiratory muscles and myocardium, which will endanger life.

A rare complication of Guillinbarre syndrome and peripheral neuropathy, mainly includes loss of limb sensation, "wearing gloves and socks", numbness, paralysis, weakness, abnormal sensation, numbness, difficulty swallowing, and some people have symptoms of facial paralysis. Immune-related encephalitis caused by immune checkpoint inhibitors is diverse and atypical. The diagnosis of is difficult and lacks specificity. It mainly involves brain diseases such as headache, fever, confusion, memory disorders, lethargy, hallucinations, epilepsy, strong neck, decreased mental state, impaired attention and disorders.

Sterile meningitis is a rare side effect, and the main symptoms include neck stiffness, fever and headache.

Transverse myelitis is mainly manifested as paraplegia, urinary retention and sensory disorders of the lower limbs.

above is a review of common and uncommon adverse reactions caused by immune checkpoint inhibitors. We must prevent early prevention of adverse reactions in immunotherapy, and both doctors and patients should try to be familiar with and understand the symptoms of adverse reaction spectrum of immune responses.



Let’s briefly review the adverse reaction spectrum of immune checkpoint treatment -

• Skin adverse reactions: the most common, the main manifestations are rash, itching and bulla.
• Gastroenterology: The most common enteritis is diarrhea, abdominal pain, bloody stools, and mucous stools.
• Respiratory tract: The most common is immune-related pneumonia, which is manifested as dyspnea, chest pain, cough, sputum and changes in CT. The treatment should be positive.
• Endocrine System: Do you still remember a relatively important hierarchical organization in the endocrine system? The hypothalamus directs the pituitary gland and pituitary gland to issue hormone commands to the thyroid, adrenal gland and gonads, so hypothyroidism, primary hypoadrenal glands, sexual dysfunction, commander pituitary inflammation, and unexplained fever, fatigue, visual impairment, and headache. Another important gland is the islet damage that secretes insulin, affecting our blood sugar.
• liver damage: the main manifestations are increased aminotransferase and bilirubin.
• Muscle and bone damage: manifested as rheumatoid arthritis, muscle pain, and elevated creatine kinase.
• Renal injury: manifested as an increase in creatinine. Some rare adverse reactions of

:

• Immune-related myocarditis: a relatively high mortality rate, manifested as chest tightness, chest pain, difficulty breathing during activity, and edema of the lower limbs. Be sure to detect and intervene early.
• Pancreatic injury: It can manifest as increased amylase and lipase, and may also have symptoms of abdominal pain.
• Eye damage: manifested as blurred vision and foreign body signs.
• Neurological damage: central nervous system damage encephalitis, meningitis, and myelitis. Peripheral neuropathy is manifested as abnormal sensation, gloves, socks, etc.
• Myasthenia gravis: Bonuses of eyelids, double shadows, muscle weakness, drinking water and cough, etc.

. Baseline examination of information should be performed before treatment, so that it can be used to evaluate whether it is a new symptom after symptoms appear in the future. Next, differential diagnosis and treatment will test oncologists. Of course, major internal medicine assistance is needed to make decisions on patient diagnosis and next treatment together. Finally, there is monitoring after adverse reactions, monitoring during and after adverse reactions, and handling complications of immunosuppressant use.

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