How Effective Is Adalimumab for Ulcerative Colitis?

Adalimumab (Humira) ^[1-2] is a self-injectable biotherapeutic drug. It has been approved by the State Food and Drug Administration (CFDA) for two indications, namely rheumatoid joints. Inflammation, ankylosing spondylitis.

In 2013, through the study of adverse events in clinical trials of adalimumab for various indications in the past 12 years, no new safety signal of adverse reactions beyond previous experience was found. In patients treated with adalimumab, the overall incidence of malignancy was the same as expected in the general population. The drug is usually used alone or in combination with methotrexate.

From January 1, 2015, 26 kinds of special medicines and special materials including adalimumab (Xu Meile) were officially included in the Qingdao city's major medical insurance list. The government, enterprises, public welfare foundations, and patients together The pattern of burden ^[3] . At the same time, in Shenzhen's supplementary medical insurance for severe and severe diseases, the biologic agent Xiu Mele (adalimumab) for the treatment of ankylosing spondylitis is included in the medical insurance catalog. Ankylosing patients pay 20 yuan per year for insurance, and drugs can be reimbursed for 70%. ^[4]

Drug Name: Adalimumab injection
Alias: Shumel
Foreign name: Adalimumab
Whether prescription drugs: prescription

Main indications: Rheumatoid arthritis, ankylosing spondylitis
Dosage form: injection
Drug type: Biologics
Licensee: Abbey
Drug type: Biologics

Introduction to adalimumab

1 Product name: Humira

2 Common name: adalimumab

3 Structural characteristics: This product is a humanized monoclonal antibody against human tumor necrosis factor (TNF), which is a dimer of human monoclonal D2E7 heavy chain and light chain bound by disulfide bonds.

3 Development and listing manufacturers: jointly developed by Cambridge Antibody Technology (CAT) in the United Kingdom and Abbott, USA, first listed in the United States in January 2003, and subsequently approved in Germany, the United Kingdom and Ireland.

Adalimumab drug description

Adalimumab indications

Adalimumab ^[5] has two indications nationwide, namely rheumatoid arthritis and ankylosing spondylitis.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease with symmetry, multiple joints, and small joints. It is known as "undead cancer". The immune system of a patient can destroy healthy joints and trigger joints. Pain, swelling, stiffness, symptoms of fatigue and weakness, stiffness and deformity at later stages, severely impaired function, and eventually loss of joint function.

Humirax is used in combination with methotrexate for treatment: anti-rheumatic drugs (DMARDs) for improving the condition, including adult patients with moderate to severe active rheumatoid arthritis who have poor response to methotrexate. The combination of Humira and Methotrexate can slow the progression of joint damage (X-ray display) in patients and improve physical function. Compared with traditional drugs, these drugs have strong and long-lasting effects, can effectively alleviate disease symptoms, imaging progress, and functional levels, and have good safety. They are suitable for various rheumatoid arthritis patients.

Ankylosing spondylitis

Ankylosing spondylitis (AS) is a disease whose main symptoms are inflammation of sacroiliac joints and spinal attachment points. Strongly associated with HLA-B27. Certain microorganisms (such as Klebsiella) share common antigens with susceptible individuals' tissues and can trigger abnormal immune responses. Ankylosing spondylitis is a chronic inflammatory disease characterized by large joints in the extremities, as well as fibrosis and ossification of the intervertebral disc fibrous rings and nearby connective tissue, as well as joint stiffness.

Humira is used in adult patients with severe active ankylosing spondylitis who do not respond well to conventional treatment. It has fast onset and good curative effect. The condition of most patients can quickly and significantly improve, such as morning stiffness, low back pain, peripheral arthritis, end tendonitis, chest enlargement, ESR and CRP. After a period of application, the patient's physical function and health-related quality of life Significant improvement, especially the recovery of some newly appeared spinal dysfunction. ^[6]

Adalimumab pharmacological effects

TNF is a cytokine that occurs naturally in inflammation and immune responses. Studies have found that TNF levels are elevated in the synovial fluid of RA patients and play an important role in pathological inflammation and joint destruction. This product can specifically bind to TNF- (and block its interaction with TNF receptors on the surface of p55 and p75 cells. In the presence of complement in vitro, this product can also lyse surface TNF-expressing cells. This product Does not bind to or inactivate lymphotoxin (TNF-). This product also regulates the biological response induced or regulated by TNF, and changes the level of adhesion molecules that cause leukocyte displacement.

Clinical evaluation of adalimumab

Four randomized double-blind studies evaluated the effectiveness and safety of this product. Participants were 18 years or older and were diagnosed with active RA according to the American College of Rheumatology (ACR) criteria. The patient had at least 6 swellings and 9 tender joints. Treatment options include subcutaneous administration of this product in combination with methotrexate (12.5 to 25 mg, Study I and Study IX), or administration of this product alone (Study II), or combination of this product with other DMARDs (Study IV). Study I included 271 patients who failed at least 1 but no more than 4 times with other DMARD treatments and had insufficient response to methotrexate. The selected patients were randomly given this product (20, 40 or 80 mg) or placebo every other week for 24 weeks.

Study II included 544 patients who had failed at least 1 time with other DMARDs. The selected patients were given this product (20 or 40 mg) or placebo alone, every other week or weekly for 26 weeks. Study included 619 patients who did not respond adequately to methotrexate. Patients received 40 mg of this product or placebo every other week, injecting placebo every other week, or 20 mg of this product every week for a total of 52 weeks. Study IV evaluated safety in 636 patients who had not received DMARD or were allowed to maintain existing treatment for at least 28 days. Patients were randomized to receive 40mg or placebo every other week for 24 weeks.

Results from Study I and Study are similar; the percentage of patients receiving 40 mg of this product every 2 weeks receiving 2%, 50%, and 70% ACR responses were 65%, 52%, and 24%, respectively. In comparison, the corresponding percentages of response in the 6-month placebo group were 13%, 7%, and 3% (53% of patients who received 40 mg of this product every other week in combination with standard treatment in Study IV) Achieved a 20% ACR response at 24 weeks, compared to only 35% of patients receiving placebo combined with standard treatment (P <0.001. No specific adverse reactions caused by the combination of this product with other DMARDs were seen.

Adalimumab adverse reactions

The most serious adverse reactions were severe infections, neurological effects, and certain malignancies of the lymphatic system. The most common adverse reactions were infections (such as nasopharyngitis, upper respiratory infections, and sinusitis), injection site reactions (erythema, itching, bleeding, pain, or swelling), headaches, and skeletal muscle pain. Most injection sites respond mildly and do not need to be discontinued.

Adalimumab precautions

Patients must be closely monitored for infections, including tuberculosis, and treatment with this product should not be started until the infection is not controlled. When the patient develops a new severe infection or hepatitis B reactivation, the treatment of this product should be interrupted until the infection is controlled. Patients with a history of infection recurrence or susceptible to infection, central nervous system demyelinating disease, malignant disease, and mild heart failure should be used with caution. Patients with blood system abnormalities, symptoms of lupus syndrome and positive for double-stranded DNA antibodies should be stopped immediately during treatment. This product has a slight impact on driving and operating the machine. It is not recommended for children, pregnancy or lactation. During the period of medication to at least 5 months after the end of treatment, women of childbearing age should contraception, breastfeeding women should not breastfeed.

Infection

Patients using TNF antagonists are more likely to develop severe infections. Impaired lung function may increase the risk of infection.

Patients must be closely monitored for infection, including tuberculosis, before, during, and after use of this product. Since the elimination of adalimumab may take up to 4 months, monitoring should be continued during this period.

Regardless of chronic active or focal active infection, treatment with this product should not be started until the infection is not controlled. Treat this product in patients with a history of tuberculosis exposure and in patients traveling in areas at high risk of tuberculosis or endemic fungal disease (eg, histoplasmosis, coccidiosis, or blastomycosis) The risks and benefits are assessed. Patients who develop infections during treatment should be closely monitored and a comprehensive diagnostic evaluation performed. When the patient develops a new severe infection or sepsis, the treatment of this product should be interrupted and treated with appropriate antibacterial or antifungal drugs until the infection is controlled. For patients with a history of recurrence of infection, or those who are susceptible to infection, including the use of immunosuppressants, doctors should be careful when considering the use of this product in these patients.

Severe infection

Data from clinical studies indicate that treatment with this product increases the risk of severe infections in patients, including sepsis or other opportunistic infections caused by bacteria, mycobacteria, invasive fungi, parasites and viruses, such as Listeria and Pneumocystis.

Other severe infections were found in clinical trials, including pneumonia, pyelonephritis, septic arthritis, and sepsis. There have also been reports of hospitalizations or deaths caused by infections.

3.Tuberculosis.

There have been reports of tuberculosis in patients receiving this product. It is worth noting that in most of the reports, the tuberculosis that appeared was of the pulmonary type, that is, disseminated.

All patients must be evaluated for active and inactive (latent) tuberculosis infection before treatment with this product. This assessment should include the patient's detailed history of tuberculosis, a history of previous contact with patients with active tuberculosis, and / or the immunosuppressive therapy currently being used. All patients must be screened appropriately, that is, a tuberculin skin test and a chest radiograph (should comply with local guidelines). It is also recommended to record the test results in the patient's medical history. Prescribers should consider the possibility of false negative tuberculin skin tests, especially those with severe illness or who are using immunosuppressants.

If the patient is diagnosed with active tuberculosis, the use of this product is prohibited.

If you suspect a latent TB infection, you must consult a physician with experience in treating TB. Under the conditions described below, doctors must carefully weigh the benefits and risks of treatment.

If inactive (latent) tuberculosis is diagnosed, appropriate tuberculosis prevention and treatment for latent tuberculosis must be performed in accordance with local treatment measures before using this product for treatment.

For those patients with several or significant tuberculosis risk factors but negative screening for latent tuberculosis, anti-TB treatment should be considered before taking this product.

For those patients with a history of latent and active tuberculosis infection, but who are not sure that they have undergone adequate treatment, they should consider giving appropriate anti-TB treatment before treatment with this product. Because during the treatment of this product, some patients with latent and active tuberculosis who had been treated before, turned back to active tuberculosis.

If during or after the treatment of this product, patients have signs / symptoms of tuberculosis infection (eg, persistent cough, wasting constitution / weight loss, low fever), the patient should be advised to see a doctor immediately.

4. Other opportunistic infections

Opportunistic infections including invasive fungal infections were observed in patients receiving this product. Delays in proper treatment because such infections have not been recognized in patients previously treated with TNF-antagonists can have fatal consequences.

Patients who have signs or symptoms of fever, discomfort, weight loss, sweating, coughing, dyspnea and / or pulmonary infiltration or other serious systemic diseases (with or without accompanying shock) should be suspected of having an invasive fungal infection, And immediately stop using this product. Consult with a physician who has experience in the diagnosis and treatment of invasive fungal infections to diagnose and implement antifungal treatment for these patients.

5. Hepatitis B reactivation

Hepatitis B reactivation has been reported with tumor necrosis factor (TNF) antagonists (including this product) in the treatment of chronic hepatitis B virus carriers (ie, surface antigen positive). Some patients have had life-threatening consequences. Patients should be tested for HBV infection before receiving this product. For patients with positive hepatitis B virus test results, it is recommended to consult a relevant professional doctor with experience in treating hepatitis B.

For those carriers of hepatitis B virus who need this product, the signs and symptoms of hepatitis B virus infection should be closely monitored throughout the treatment process and months after treatment. To date, there is no data on hepatitis B virus carriers receiving a combination of antiviral and TNF antagonists to prevent hepatitis B reactivation. If patients have reactivation of hepatitis B, treatment with this product should be discontinued and effective antiviral treatment should be taken with appropriate supportive treatment.

6. Nervous system

From the clinical symptoms and / or radiological examination results, TNF antagonists including this product rarely cause the occurrence and deterioration of central nervous system demyelinating diseases, including multiple sclerosis, peripheral demyelinating diseases including Green- Barrie syndrome. For patients who have or are currently suffering from demyelination of the central and peripheral nervous system, doctors should take extra care when giving this product.

7. Allergic reactions

At the clinical research stage, there were no reports of serious adverse events caused by subcutaneous injection of this product in patients, and non-serious allergic reactions caused by this product were also uncommon. After marketing, serious allergic reactions (including allergies) caused by the use of this product are rarely reported. If the patient has an allergic reaction and other severe allergic reactions, the drug should be stopped immediately and appropriate treatment should be taken.

The needle surface of the syringe is covered with natural rubber (latex). Patients with latex allergies may experience severe allergic reactions when using this product.

8. Immunosuppression

Among the 64 patients with rheumatoid arthritis who studied this product, there is no evidence that this product inhibits delayed allergic reactions, immunoglobulin levels, and does not change T cells, B cells, and NK (natural kill) Number of cells, monocytes / macrophages and neutrophils.

9. Malignant diseases and abnormal lymphocytic hyperplasia

In the control portion of the clinical study of TNF antagonists, malignant lesions (including lymphomas) occurred in patients treated with TNF antagonists compared to the control group, but the incidence was very low. Leukemia cases have been reported in patients receiving TNF antagonists after marketing. For patients with rheumatoid arthritis who have chronically active inflammatory lesions, the risk of lymphoma and leukemia increases, which complicates risk assessment. It is currently known that the risk of lymphoma, leukemia, or other malignant disease in patients receiving TNF antagonists cannot be ruled out.

Post-market surveillance, including this product, found that some children, adolescents, and young adults (up to 22 years of age) receiving TNF antagonist therapy (18 years of age at the beginning of treatment) have developed certain deadly malignancies. Half are lymphomas. Other manifestations are various malignancies, including rare immunosuppression-related malignancies. The risk of malignant lesions in children and adolescents receiving TNF antagonists cannot be ruled out.

After marketing, adverse reactions to liver and spleen T-cell lymphoma are rare. This rare T-cell lymphoma is a rapidly progressing disease that is often fatal. When this product is combined with azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease, some young adult patients develop liver and spleen T cell lymphomas. Careful consideration should be given to the potential risks of combining this product with azathioprine and 6-mercaptopurine. Therefore, the risk of hepatosplenic T-cell lymphoma in patients treated with this product cannot be ruled out.

So far, there have been no studies on the use of this product in patients with malignant disease, or the continued treatment of this product in patients who have developed malignant disease. Therefore, the treatment of this product in such patients should be given more consideration.

For all patients, especially those who have received extensive immunosuppressive therapy or photochemical treatment of psoriasis, the skin should be checked for non-melanin skin cancer before treatment with this product.

In an exploratory clinical study, another TNF antagonist, infliximab, was evaluated and the results showed that patients using infliximab had severe chronic obstructive disease compared with controls. Patients with lung disease (COPD) are more likely to have malignant lesions, and most of these lesions occur in the lungs or head and neck. All patients had a history of heavy smoking. Therefore, care should be taken when using TNF antagonists in patients with COPD, and heavy smoking may increase the risk of malignancy in patients.

Based on available data, it is unclear whether adalimumab has an effect on the risk of atypical hyperplasia or colon cancer. All patients with ulcerative colitis with atypical hyperplasia or increased risk of colon cancer (for example, patients with long-term ulcerative colitis or primary sclerosing cholangitis), or patients with a history of atypical hyperplasia or colon cancer Screen for atypical hyperplasia before administration and throughout the course of the disease. Evaluation can be based on local treatment guidelines and should include at least colonoscopy and tissue biopsy.

10. Hematological response

In cases where TNF antagonists are used, reports of whole blood cells including aplastic anemia are rare. A few reports of adverse hematological reactions when using this product include clinically significant reductions in blood cells (eg, thrombocytopenia, leukopenia). If the patient develops signs and symptoms of cachexia (for example, persistent fever, bruises, bleeding, pale skin), they should be treated immediately. For patients who have been diagnosed with a hematological abnormality, the use of this product should be stopped immediately.

11. Vaccination

Among 226 adult rheumatoid arthritis subjects treated with adalimumab and placebo, they had similar antibody responses to the standard 23-valent pneumococcal polysaccharide vaccine and the trivalent influenza virus vaccine. There have been no reports of secondary infection transmission from live vaccines in patients treated with this product. In addition to live vaccines, patients using this product can receive vaccination at the same time.

12. Congestive heart failure

In another clinical study of TNF antagonists, deterioration of congestive heart failure and increased mortality due to congestive heart failure were observed. Cases of worsening congestive heart failure have also been reported in patients receiving this product. For patients with mild heart failure (NYHA Class I / II), care should be taken when using this product. Moderate to severe heart failure is a contraindication for this product. If you have symptoms of congestive heart failure, or if your symptoms have worsened in the past, you should stop using this product.

13. Autoimmune process

The drug treatment of this product will lead to the formation of autoantibodies. The effect of long-term treatment with this product on autoimmune diseases is unclear. If the patient develops symptoms of lupus-like syndrome after treatment with this product and the double-stranded DNA antibody is positive, treatment with this product should be stopped immediately.

14. Simultaneous use of TNF antagonists and anakinra

In clinical studies using ananercept and other TNF antagonists, etanercept, severe infections were observed and did not improve clinical efficacy compared to etanercept alone. According to the characteristics of adverse reactions in the combination use of etanercept and anakinin, similar toxicity may also occur when anakinin is used in combination with other TNF antagonists. Therefore, the combined use of this product and anakinin is not recommended.

15. Simultaneous use of TNF antagonists and abatacept

Compared with TNF antagonists alone, the combined use of TNF antagonists and abatacepte increases the risk of infection, including severe infections, but does not improve clinical efficacy. It is not recommended to use this product in combination with Ababasset.

16. Surgery

Experience on the safety of surgery in patients receiving this product is limited. When planning surgery for patients, consider the long half-life of adalimumab. When patients receiving this product need surgery, they should pay close attention to the patient's infection and take appropriate measures. Arthroplasty safety experience in patients receiving this product is also limited.

17. Small bowel obstruction

Ineffective for Crohn's disease, it means that there may be fixed fibrous stenosis in the intestinal lumen and surgery is needed. Existing data show that this product will not cause intestinal stenosis or cause it to worsen.

18. Seniors

Patients over the age of 65 (3.7%) receiving this product were more likely to develop severe infections than those under 65 (1.4%). Some of them have fatal consequences. Therefore, the treatment of elderly patients should pay special attention to the risk of infection.

19. Impact on the ability to drive and operate machines

This product has a slight impact on driving and operating the machine. Treatment with this product may cause dizziness (including dizziness, visual impairment and fatigue).

Adalimumab drug interactions

1. In patients with rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, this product is treated as a single drug and not used simultaneously with methotrexate;

2. It is not recommended to use this product in combination with anakin.

3. It is not recommended to use this product in combination with abatacepte;

4. Drug compatibility. Due to no drug compatibility studies, this product cannot be mixed with other drugs.

Adalimumab usage and dosage

The treatment of this product should be carried out under the supervision of a specialist with experience in the diagnosis and treatment of rheumatoid arthritis and ankylosing spondylitis. Patients who are deemed appropriate by the treating physician and who can perform medical follow-up if necessary, can be self-administered after being trained in proper injection techniques.

1. Adults-For adult patients with rheumatoid arthritis, the recommended dosage is 40 mg of adalimumab, given as a single subcutaneous injection every two weeks. Methotrexate should be continued during the treatment of this product. Glucocorticoids, salicylic acid non-steroidal anti-inflammatory drugs or analgesics can continue to be used during the treatment of this product. In the case of single-drug treatment, if the therapeutic effect of some patients decreases, the dosage can be increased to 40 mg of adalimumab per week to improve the efficacy. Discontinuation of Dosage-The available data indicate that re-use of this product after an interval of 70 days or more will achieve the same level of clinical response and safety as before the interruption of dosing.

For adult patients with ankylosing spondylitis, the recommended dosage is 40 mg of adalimumab, administered subcutaneously every two weeks. For all of the above indications, the available data indicate that a clinical response is usually obtained within 12 weeks of treatment, and that patients who have not had a clinical response during that period of care should be carefully considered to continue treatment.

2. Elderly patients-no dose adjustment is needed.

3. Patients with hepatic and / or renal dysfunction-this product has not been studied in this patient population and no dosage recommendations have been made.

Adalimumab preparation

This product is a single-use 1mL glass pre-filled syringe. Contains a sterile preservative-free injection solution, which can provide 40mg (0.8mL) of this product.