ADVAIR DISKUS REVIEWS

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What is ADVAIR DISKUS?
What is this medicine?
FLUTICASONE; SALMETEROL inhalation is for treating asthma that is not controlled with other asthma medicines or when more than one treatment is necessary. Fluticasone is a corticosteroid which decreases inflammation in the lungs. Salmeterol helps open the airways in the lungs. This medicine is intended for regular use. It will not cure your condition, but when used regularly it can open up your air passages and make breathing easier. It will not relieve an acute asthma attack. Fluticasone; salmeterol can be used along with other inhaled or oral asthma medications.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
an asthmatic attack or bronchospasm
chicken pox or measles (recent exposure or infection)
diabetes
heart disease including high blood pressure, irregular heart beat, blockage in heart vessels
immune system problems
infection, especially fungal infection or tuberculosis
liver disease
osteoporosis or other bone disease
overactive thyroid
pheochromocytoma
seizures
an unusual or allergic reaction to Fluticasone, Salmeterol, other corticosteroids, other medicines, foods, dyes, or preservatives
pregnant or trying to get pregnant
breast-feeding
How should this medicine be used?
DO NOT use this medicine for an asthma attack. If you have severe onset or worsening of cough, wheezing, chest tightness, and/or shortness of breath seek immediate medical attention. Always keep a short-acting asthma medication such as albuterol on hand for asthma attacks.
This medicine is for inhalation through the mouth. Shake the inhaler well for 5 seconds before each spray. Prime the inhaler before the first use with 4 test sprays pointing away from your face. If you drop the inhaler or of it has not been used for 4 weeks, prime it with 2 test sprays pointing away from your face. Avoid contact with eyes. After using the inhaler, rinse your mouth with water to minimize build-up of medicine; do not swallow the water. Clean your inhaler at least once a week. Never place the inhaler in water to determine how much medicine is in it. Do not use more than the recommended dose.
Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.
NOTE: This medicine is only for you. Don’t share it with others.
What if I miss a dose?
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, take only that dose and continue with your regular schedule, spacing doses evenly. Do not use double or extra doses.
What may interact with this medicine?
arsenic trioxide
astemizole
bepridil
beta-blockers, often used for high blood pressure or heart problems
caffeine
certain antibiotics (such as clarithromycin, erythromycin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, linezolid, moxifloxacin, sparfloxacin)
chloroquine
cisapride
droperidol
halofantrine
levomethadyl
medicines for colds and breathing difficulties
medicines for heart disease or high blood pressure
medicines known as MAO inhibitors, such as phenelzine (Nardil®), tranylcypromine (Parnate®), isocarboxazid (Marplan®), and selegiline (Carbex®, Eldepryl®)
medicines to control heart rhythm (examples: amiodarone, disopyramide, dofetilide, flecainide, procainamide, quinidine, sotalol)
medicines for treating depression or mental illness (amoxapine, haloperidol, maprotiline, pimozide, phenothiazines, risperidone, sertindole, tricyclic antidepressants, ziprasidone)
methadone
pentamidine
probucol
some medicines for weight loss (including some herbal products, ephedra, ephedrine, dextroamphetamine)
steroid hormones such as dexamethasone, cortisone, hydrocortisone
terfenadine
theophylline
thyroid hormones
water pills or diuretics
Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.
What should I watch for while taking this medicine?
Visit your prescriber or health care professional for regular checks on your progress. Carry an identification card with your name, the type and dose of medicine you are taking, and your prescriber’s name and address. It can take up to 2 weeks before you see the full effect of this medicine.
Check with your prescriber or health care professional if your symptoms do not improve. Seek emergency medical attention if your breathing problems get worse quickly while taking this medicine, or if your rescue inhaler (like albuterol) does not help your breathing. If you find that you are using your rescue inhaler more than normal or it is not as effective in treating your symptoms, you should contact your health care professional as soon as possible. You may need a change of therapy or may be having worsening of your lung condition. Do not stop using this medicine except on your prescriber’s advice.
Using your inhalers regularly as prescribed will help control your symptoms; try not to run out of your medications. It is recommended that you keep an extra refill of your inhalers on hand in case you need them.
Tell your prescriber or health care professional if you are exposed to anyone with measles or chickenpox, or if you develop sores or blisters that do not heal properly.
People who are taking certain dosages of this medicine may need to avoid getting certain vaccines or may need to have changes in their vaccination schedules to ensure adequate protection from certain diseases. Make sure to tell your prescriber or health care professional that you are taking fluticasone; salmeterol before receiving any vaccine.
If you are going to have surgery tell your prescriber or health care professional that you are using this medicine.
What side effects may I notice from this medicine?
Side effects that you should report to your prescriber or health care professional as soon as possible:
chest pain
dizziness or lightheadedness
fever or chills
skin rash and itching (hives)
sore mouth with white patches in the mouth or throat
troubled breathing or wheezing
unusual swelling
unusual tiredness or weakness
vision problems
vomiting
Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
coughing, hoarseness, throat irritation
diarrhea
headache
nausea
nervousness
sore throat
stomach upset
stuffy nose
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15—30 degrees C (59—86 degrees F) with mouthpiece facing down. Keep away from heat or open flames.
Uses
This product is used to control and prevent symptoms (wheezing and shortness of breath) caused by asthma or ongoing lung disease (chronic obstructive pulmonary disease-COPD, which includes chronic bronchitis and emphysema). It contains 2 medications: fluticasone and salmeterol. Fluticasone belongs to a class of drugs known as corticosteroids. It works by reducing the irritation and swelling of the airways. Salmeterol belongs to the class of drugs known as long-acting beta agonists. It works by opening airways in the lungs to make breathing easier. Controlling symptoms of breathing problems can decrease time lost from work or school.
When used alone, long-acting beta agonists (such as salmeterol) may rarely increase the risk of serious (sometimes fatal) asthma-related breathing problems. However, combination inhaled corticosteroid and long-acting beta agonists, such as this product, do not increase the risk of serious asthma-related breathing problems. For asthma treatment, this product should be used when breathing problems are not well controlled with one asthma-control medication (such as inhaled corticosteroid) or if your symptoms need combination treatment.
Before using this medication, it is important to learn how to use it properly. This medication must be used regularly to be effective. It does not work right away and should not be used to relieve sudden asthma attacks. If an asthma attack occurs, use your quick-relief inhaler (such as albuterol, also called salbutamol in some countries) as prescribed.
How to use Advair Diskus Blister, With Inhalation Device
Read the Patient Information Leaflet and Instructions for Use provided by your pharmacist before you start using this medication and each time you get a refill. Follow the illustrated directions for the proper use of this medication. If you have any questions, ask your doctor or pharmacist.
Use this device in a level, flat position. Inhale this medication by mouth as directed by your doctor, usually twice daily (in the morning and evening, 12 hours apart). You may or may not taste/feel the drug when you inhale. Either is normal. Do not exhale into the device.
Do not take the inhaler apart or wash the mouthpiece or any part of the device. Close the device after each use.
If you are using other inhalers at the same time, wait at least 1 minute between the use of each medication, and use this drug last.
Gargle and rinse your mouth with water after each use of this medication to help prevent irritation and yeast infections (thrush) in the mouth and throat. Do not swallow the rinse water.
The dosage is based on your medical condition, age, and response to treatment.
Use this medication regularly in order to get the most benefit from it. This medication works best if used at evenly spaced times. To help you remember, use it at the same times each day. Do not increase your dose, use this medication more often, or stop using it without talking with your doctor. Also, do not use other long-acting beta agonists while using this medication.
If you have been using a quick-relief inhaler (such as albuterol, also called salbutamol in some countries) on a regular daily schedule (such as 4 times daily), you must stop this schedule and only use the quick-relief inhaler as needed for sudden shortness of breath/asthma attacks. Consult your doctor for details.
If you are regularly using a different corticosteroid taken by mouth (such as prednisone), you should not stop using it unless directed by your doctor. You may have withdrawal symptoms if the drug is suddenly stopped. Some conditions (such as asthma, allergies) may become worse when the drug is suddenly stopped. To prevent withdrawal symptoms (such as weakness, weight loss, nausea, muscle pain, headache, tiredness, dizziness), your doctor may direct you to slowly lower the dose of your old medication after you begin using this product. Consult your doctor or pharmacist for more details, and report any withdrawal reactions right away. See also Precautions section.
It may take 1 week or longer before you get the full benefit of this drug. Tell your doctor if your condition does not improve or if it worsens.
Learn which of your inhalers you should use every day (controller drugs) and which you should use if your breathing suddenly worsens (quick-relief drugs). Ask your doctor ahead of time what you should do if you have new or worsening cough or shortness of breath, wheezing, increased sputum, worsening peak flow meter readings, waking up at night with trouble breathing, if you use your quick-relief inhaler more often (more than 2 days a week), or if your quick-relief inhaler does not seem to be working well. Learn when you can treat sudden breathing problems by yourself and when you must get medical help right away.
Side Effects
Hoarseness, throat irritation, headache, or stomach upset may occur. If any of these effects persist or worsen, tell your doctor promptly.
This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.
Infrequently, this medication may cause severe sudden worsening of breathing problems/asthma immediately after use. If you have sudden worsening of breathing, use your quick-relief inhaler and get medical help right away.
Tell your doctor right away if any of these unlikely but serious side effects occur: white patches on tongue/in mouth, signs of infection (such as fever, persistent sore throat), mental/mood changes (such as nervousness), trouble sleeping, vision problems (such as blurred vision), increased thirst/urination, muscle cramps, shaking (tremors).
Get medical help right away if any of these rare but seriouschest pain, fast/irregular heartbeat, severe dizziness, fainting, seizures.
A very serious allergic reaction to this product is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
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Treatment for Allergies

Treatment for Allergies

Allergy Symptoms & Treatments : How to Cure Dust Allergies Treatment for Allergies Allergy Drugs
Besides nasal sprays that relieve sinus-related symptoms, there are medications that can help reduce your body’s reaction to allergens. These drugs, both OTC and prescription, can be taken as liquids or pills.
Common allergy medicines include: Antihistamines
Antihistamines work by blocking the effects of histamine (a chemical in the body that can cause allergy symptoms). They’re sometimes combined with other types of drugs.
Examples of antihistamines include:
Common side effects of antihistamines include: Drowsiness or sleepiness Dry mouth, nose, or throat Increased appetite and weight gain Upset stomach Changes in vision Feeling nervous, excited, or irritable
You may need to avoid certain foods, such as grapefruit and grapefruit juice, while taking an antihistamine because they can affect how these drugs work in your body. Alcohol may worsen certain side effects.
Talk to your doctor about any symptoms or concerns you may have. Decongestants
These medications relieve congestion by shrinking swollen nasal tissues and blood vessels. They are often prescribed along with antihistamines.
Examples of decongestants include: Mast Cell Stabilizers
These medications block the release of immune system chemicals (histamine, leukotriene) that trigger allergic reactions of the eyes (allergic conjunctivitis) or nasal passageway. They are better at preventing than treating allergic symptoms, so they are given to patients with seasonal allergies starting about two weeks before allergy season begins.
Examples of mast cell stabilizers include: Alomide (lodoxamide) — eye drops Nasalcrom (cromolyn sodium) — nasal spray Steroids
These drugs can help reduce inflammation in the nasal passages, lungs, and skin. Steroid use can cause a wide range of side effects and needs to be closely monitored by your doctor.
Prednisone is a corticosteroid, or man-made form of the steroid that the body produces to fight illnesses and injuries. It is prescribed alone or in combination with other medication to treat severe allergic reactions and many other conditions. It is given in liquid or tablet form. (5) Leukotriene Modifiers
Leukotrienes are chemicals the body releases as a response to allergens. They can cause airway constriction, inflammation in the lungs, and increased mucus production.
Leukotrine modifiers are a class of drugs that work by blocking the actions of leukotrienes in the body. They are used to treat symptoms of asthma and, in the case of the drug Singulair (montelukast), allergic rhinitis. Anti-Immunoglobulin E (IgE) Therapy
Xolair (omalizumab) helps decrease allergic responses in the body by reducing the number of Ige (immunoglobulin E) antibodies the immune system produces in response to an allergen. (6)
It is used to treat moderate to severe asthma that is caused by allergies in adults and children who are at least 6 years old.
The drug is injected under the skin, and it is usually given every two or four weeks. Epinephrine
Epinephrine is used to treat anaphylaxis — a severe, life-threatening allergic reaction — until emergency treatment can be administered.
Anaphylactic reactions are commonly caused by Foods, such as peanuts, tree nuts, wheat, fish, milk, and eggs Medication, especially penicillin and stings Latex
Prescribed by your doctor, epinephrine comes as a single dose in an auto-injector (such as an EpiPen). An injection of epinephrine quickly improves breathing, stimulates the heart, raises dropping blood pressure, reverses hives, and reduces swelling of the face, lips, and throat. Video: Allergies to Cats & Recurring Sinus Infections : Treating Allergies Treatment for Allergies images 2019 year – Treatment for Allergies pictures Treatment for Allergies recommendations photo Treatment for Allergies photo Treatment for Allergies new picture pictures Treatment for Allergies Watch Treatment for Allergies video Discussion on this topic: Treatment for Allergies , treatment-for-allergies/ , treatment-for-allergies/ Related News

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Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer

<h1>Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer</h1>

Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT03776487 Recruitment Status : Not yet recruiting First Posted : December 14, 2018 Last Update Posted : December 14, 2018 Information provided by (Responsible Party): M.D. Anderson Cancer Center Study Description Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: This pilot phase I/II trial studies the side effects and how well nivolumab and ipilimumab in combination with chemotherapy and radiation therapy work in treating patients with gastric cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Intensity-modulated radiation therapy uses thin beams of radiation of different strengths aimed at the tumor from many angles. This type of radiation therapy may reduce the damage to healthy tissue near the tumor. Giving nivolumab, ipilimumab, chemotherapy and radiation therapy may work better in treating patients with gastric cancer. Condition or disease Intervention/treatment Phase Clinical Stage 0 Gastric Cancer AJCC v8 Clinical Stage 0 Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage I Gastric Cancer AJCC v8 Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IIB Gastric Cancer AJCC v8 Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IVA Gastric Cancer AJCC v8 Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Gastric Adenocarcinoma Localized Gastric Carcinoma Localized Gastroesophageal Junction Adenocarcinoma Pathologic Stage 0 Gastric Cancer AJCC v8 Pathologic Stage 0 Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage I Gastric Cancer AJCC v8 Pathologic Stage IA Gastric Cancer AJCC v8 Pathologic Stage IA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IB Gastric Cancer AJCC v8 Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIA Gastric Cancer AJCC v8 Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIB Gastric Cancer AJCC v8 Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIA Gastric Cancer AJCC v8 Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Drug: Fluorouracil Radiation: Intensity-Modulated Radiation Therapy Biological: Ipilimumab Biological: Nivolumab Drug: Oxaliplatin Procedure: Therapeutic Conventional Surgery Phase 1 Phase 2 Detailed Description: PRIMARY OBJECTIVES: I. To evaluate the safety and toxicity profile of intravenous nivolumab in combination with ipilimumab after standard chemotherapy and followed by intravenous nivolumab in combination with fluoropyrimidine and intensity-modulated radiation therapy (IMRT) for the treatment of localized gastroesophageal junction (GEJ) and/or gastric cancer. SECONDARY OBJECTIVES: I. To assess the efficacy of double checkpoint inhibition (nivolumab + ipilimumab) followed by nivolumab plus chemoradiation. II. To assess the overall safety and tolerability of adjuvant nivolumab in subjects with resected GEJ or gastric cancer. III. To evaluate disease free survival (DFS). IV. To explore changes in tumor stroma profile before and after immunotherapy and radiation therapy. V. To bank tumor and blood specimen for future correlative analysis, including, but not limited to, biomarker analysis. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy. Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 and 84 days, every 12 weeks for 2 years, then every 6-12 months for up to 3 years. Study Design Go to
Treatment Official Title: Pilot Study of Dual Checkpoint Inhibition Followed by Immuno-Chemoradiation in Patients With Resectable Gastric Adenocarcinoma (Concept ID 2016-NIV-0551) Estimated Study Start Date : Arms and Interventions Go to
Intervention/treatment Experimental: Treatment (chemotherapy, immunotherapy, IMRT) INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy. Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Drug: Fluorouracil Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody BMS-734016 Undergo partial or total gastrectomy and lymphadenectomy Outcome Measures Go to Primary Outcome Measures : Incidence of adverse events [ Time Frame: Up to 30 days ] The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately. Secondary Outcome Measures : Response rates [ Time Frame: Up to 5 years ] Response rates will be estimated along with the corresponding exact 95% confidence interval. Incidence of adverse events in patients with resected gastroesophageal junction (GEJ) or gastric cancer [ Time Frame: Up to 5 years ] The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately. Disease-free survival [ Time Frame: From the date of surgery until disease relapse or death, whichever occurred first, assessed up to 5 years ] Will be estimated using the method of Kaplan and Meier. Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Criteria Inclusion Criteria: Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study. All subjects must have localized/eligible for surgery gastric cancer (GC) or GEJ carcinoma type III, with negative peritoneal washing. Subjects must have histologically confirmed predominant adenocarcinoma. The documentation of GEJ involvement can include biopsy, endoscopy, or imaging. Subject must be previously untreated with systemic treatment (including HER 2 inhibitors) given as primary therapy for advanced or metastatic disease. No prior neoadjuvant chemotherapy, immunotherapy, radiotherapy and/or chemoradiotherapy are permitted. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days of treatment initiation). Platelets >=100,000/mcL (within 28 days of treatment initiation). Hemoglobin >= 9 g/dL or > 5.6 mmol/L; if patient is not actively bleeding and has hemoglobin of = 9g/dL (within 28 days of treatment initiation). Serum creatinine = 60 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (measured via 24-hour urine collection) (within 28 days of treatment initiation). Creatinine clearance should be calculated per institutional standard. Serum total bilirubin =< 1.5 X ULN (1.5 mg/dL or 25.65 umol/L) OR direct bilirubin < ULN for subjects with total bilirubin levels < 1.5 X ULN. Except patients with Gilbert's disease (< 3 X ULN) (within 28 days of treatment initiation). Aspartate aminotransferase AST (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR = 3 mg/dL (within 28 days of treatment initiation). Prothrombin Time (PT) < 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time PTT is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin Time (aPTT) 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally. White blood cell (WBC) < 2000/uL. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. hepatitis B surface antigen (HBsAg Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if hepatitis C virus- ribonucleic acid [HCV-RNA] negative). History of allergy or hypersensitivity to study drug components. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Patients with serious or uncontrolled medical disorders. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03776487 Contacts

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Diagnosing and Managing Inflammatory Bowel Disease

<h1>Diagnosing and Managing Inflammatory Bowel Disease</h1>

Diagnosing and Managing Inflammatory Bowel Disease

There is a high prevalence of inflammatory bowel disease (IBD) in Australia, and due to improving therapies there are an increasing number of highly functioning patients being managed in the community. The role of the general practitioner is paramount in the coordination and ongoing monitoring of this chronic disease, while working closely with the gastroenterologist.
Inflammatory bowel disease is a complex disease to both diagnose and manage, posing a number of challenges to those involved in the care of the patient. We will briefly outline the modalities in diagnosis, updates in management and ancillary factors that contribute to the overall well-being of the patient with IBD.
PREVALANCE
It is estimated that approximately 75000 Australians are living with IBD, with over 1622 new cases diagnosed every year.1 Australia has among the highest reported incidence of IBD worldwide, posing a significant healthcare burden – hospital costs for 2012 were estimated to be more than $100 million a year.2
Crohn’s disease occurs equally in both males and females, whereas ulcerative colitis occurs 20 to 30% more in males than females.3
DIAGNOSIS
IBD can be diagnosed at any age, but has a peak prevalence in Australia among the 30 to 39-year-old otherwise healthy active people. The signs and symptoms vary dramatically among patients, often leading to a clinical predicament and delay in diagnosis.
In addition to diagnosis, stratifying patients earlier in the disease course is crucial in identifying high risk patients and therefore commencing early aggressive treatment, where indicated, to avoid later complications.
While there are many overlying pathological and radiological features of Crohn’s disease and ulcerative colitis, the main distinguishing feature is site of involvement, with Crohn’s disease potentially affecting any region from the mouth to anus.
Symptoms usually correlate with location and extent of inflammation, however often there is a discordance and investigations are required to qualify these objectively.4Challenges arise when patients who seem clinically well are in fact concealing active inflammation, highlighting the importance of close and constant monitoring.
Patients with ulcerative colitis predominantly present with bloody diarrhoea, with associated abdominal pain, urgency or tenesmus. Symptoms of Crohn’s disease vary significantly given the potential diverse locations of involvement but are typically abdominal pain, diarrhoea and weight loss.
Systemic features such as fatigue, anorexia and fever are more common compared with ulcerative colitis, and can sometimes reflect underlying weight loss, nutritional deficiencies or malabsorption. Strictures, fistulae or abscesses are crucial to identify on history as these features often correlate with more severe disease.5
Delays in diagnosis often arise due to IBD sharing symptoms with other more common and less sinister conditions such as irritable bowel syndrome, gastroenteritis or functional disorders. Temporal and alarm features are important to recognise, and can be used in conjunction with investigations to best delineate the disease.
There are a number of standardised classification systems that can be utilised in clinical decision making.
Crohn’s disease
The Crohn’s Disease Activity Index (CDAI) is an estimate of the clinical severity of the disease, whereas disease phenotype (degree of inflammation) is classified according to the Montreal Classification.6 The goal of therapy with Crohn’s disease is to achieve a CDAI of < 150 for at least 12 months.
Ulcerative colitis
The European Crohn’s and Colitis Organisation (ECCO) and the American College of Gastroenterology classify UC using the Montreal Classification, based on Truelove and Witts’ criteria. The goal of therapy with ulcerative colitis is to achieve complete resolution of symptoms and endoscopic mucosal healing.
INVESTIGATIONS
There is unfortunately no one reliable test to diagnose IBD, but rather a concert of laboratory, imaging and endoscopic investigation. Simple laboratory tests can be done to evaluate the severity of inflammation and any associated deficiencies.
Blood examination
Basic investigations outlined below are helpful in ascertaining the presence and severity of disease, and are helpful to have done prior to referring to the gastroenterologist.
Full blood count: anaemia, elevated white cell count or platelets suggestive of inflammation. 7
Inflammatory markers: elevated CRP and ESR.
Biochemistry: low albumin (inflammation and malnutrition), impaired renal function due to dehydration, electrolyte imbalances.
Faecal testing
Faecal calprotectin: most widely used neutrophil-derived protein biomarker. Highly sensitive, non-invasive marker of intestinal inflammation.8 It is utilised as a non-invasive marker of disease monitoring in patients on therapy for IBD, as well as in helping with diagnosis by excluding IBS. Limiting factors include potential for false positives, and that it is not yet MBS rebateable in Australia (costs the patient approximately $42).
Stool microscopy, culture and sensitivity: Clostridium difficile , or other bacterial, viral or parasitic organisms must be excluded when a patient presents with symptoms suggestive of IBD. Often in those with already established IBD, infectious gastroenteritis can, in fact, trigger an IBD flare or can occur concurrently. Furthermore, IBD patients on immunosuppression are more susceptible to infections and it is important to exclude these when they present with suggestive symptoms. C. difficile in particular has a higher incidence in patients with IBD, and is associated with higher mortality rates.9
Specialised testing
If there is a high suspicion for IBD after consultation with the GP and above investigations, then early specialist referral is encouraged in order to arrange for more specific and targeted investigations such as endoscopy and/or radiological tests. Once referred, the gastroenterologist will evaluate the urgency of further investigations and accordingly arrange for gastroscopy and/or colonoscopy/ileoscopy for biopsies and histological diagnosis. Where there is suspected small bowel involvement, they may also arrange for an MRI enterography or video capsule endoscopy. Perianal disease (abscesses or fistulae) is also further evaluated with MRI and generally warrant surgical involvement.3,4
Once a diagnosis of IBD has been established by the specialist after correlation with clinical, histological and imaging data, the disease is generally stratified and the best management strategy is identified.
MEDICAL MANAGEMENT
With the advent of new biologic agents, treatment targets expand beyond just resolution of clinical symptoms. The current paradigm of treatment in IBD is “Treat to Target” (T2T), where, if defined targets (clinical, biochemical or composite target) are not achieved, then treatment is either intensified or switched.11
As the treatment of IBD is very complex and individualistic, we will only briefly summarise when and which medications are used in Australia, and instead focus on the role of the GP in monitoring patients on these treatments and when to escalate their care.
Monitoring
Due to the significant side effect profile of medications, as well as the often indolent nature of the disease, IBD requires close biochemical monitoring, for which the GP plays a pivotal role. Furthermore, as the goals of therapy have now been maximised, there are greater expectations to optimise outcomes and minimise treatment failure.
Thiopurine metabolite testing
Up to 50% of patients do not respond to thiopurine dosing, and up to 20% will experience one or more adverse effects. The table aboveoutlines the target 6TGN (associated with clinical efficacy) and 6MMP (associated with hepatotoxicity) results. In order to detect adverse events early, it is crucial to perform close monitoring of the patient’s blood biochemistry once commenced on treatment. This involves initially performing FBC, EUC and LFTs fortnightly for four weeks, monthly for four months, then every three to four months long term.12 The other advantage of testing metabolites is to identify patients who are non-adherent with therapy, which often only requires patient education in order to optimise outcomes.
Therapeutic drug monitoring
This is becoming increasingly common practice among gastroenterologists,and helps guide whether dose adjustment or class switching is required. It should only be performed and acted on by the gastroenterologist.
Faecal calprotectin
As discussed earlier, faecal calprotectin is quite a useful and non-invasive tool in monitoring the disease and response to therapy. It should not, however, replace clinical judgement but rather be integrated into the armamentarium utilised by gastroenterologists managing IBD.13
Managing flares
Early identification of a disease flare is crucial in preventing serious complications such as bowel obstruction or perforation. Often, most patients are well-attuned to their symptoms and know when they are having a flare.
Other times, it is the discretion of the medical practitioner to determine whether the patient will benefit from hospitalisation.
Some features in the history that would point to emergency referral would be severe abdominal pain and/or fevers with frequent bloody diarrhoea (for example more than six episodes/day), or inability to tolerate oral intake.
In such instances, patients benefit from emergent imaging and commencement of intravenous hydrocortisone.
For patients with increased stool frequency or tolerable abdominal pain, it would be appropriate to consider commencing them on prednisone 40mg daily orally and to inform their gastroenterologist in order to expedite follow up within the next week. Performing basic bloods tests, including inflammatory markers, can assist the specialist in deciding the next best step in management.
NON-PHARMACOLOGICAL MANAGEMENT
Probiotics: there are no robust studies supporting the use of probiotics in inducing remission, preventing relapses or post-operative recurrence of Crohn’s disease. There is some historical data suggesting that probiotics have shown to safely maintain remission in ulcerative colitis, or those with recurrent or refractory pouchitis. Current theory is that probiotics may have a role in treating gastrointestinal conditions, boosting immunity and preventing or slowing the development of certain types of cancer.
We can only assure patients that there is a lack of evidence-based guidelines and while probiotics use seems safe, we cannot conclude that they are a feasible alternative to pharmacological treatment.14 It needs to be reiterated to patients that they are by no means a substitute, but can be used as an adjunct should the patient choose to. Gastroenterologists do not routinely recommend the use of probiotics in IBD.
In a similar vein, there are only poor quality studies supporting the use of herbal and nutritional supplements. In fact some supplements, such as St John’s Wort, can interact with immunosuppressive agents and interfere with their efficacy.15
Diet: There are no strict rules with diet in IBD. Generally, we advise patients with Crohn’s disease to adhere to a low residue diet. There is no evidence that certain food groups trigger flares, although each individual may subjectively experience symptoms of gastrointestinal irritation with certain foods. In these scenarios, it is generally advised that the patient avoid that certain food but be reassured that it has not contributed to increased inflammation or worsened disease activity. Referral to a dietician is helpful for the patient in determining a diet that best suits them. In general, the aim is to avoid being malnourished.
HOLISTIC CARE
The management of IBD requires a multi-disciplinary approach with vigilant monitoring thereby anticipating and preventing complications in order to maximise patient outcome. GPs play a big role in early diagnosis, supporting the patient psychologically, as well as observing response and adherence to maintenance therapy. Given the life-long and complex nature of this disease, patients would certainly benefit from generating an action plan in conjunction with their gastroenterologist and GP in order to recognise problems early. Some important factors to consider from a preventative medicine perspective will be briefly outlined below.
Vaccination
Vaccination recommendations should be guided by the gastroenterologist. Practice is currently based on recommendations, however, evidence-based data remains low. Several studies have, however, documented the poor uptake of routine vaccinations among patients with IBD, with common reasons being patient lack of awareness and fear of side effects. It is important that both the gastroenterologist and GP reinforce the importance of remaining up to date with their vaccination schedule, and reassuring them in particular that there is no evidence correlating increased disease activity post vaccination.16
The table above outlines common vaccinations, targeted patients, and appropriate timing of administration. In general, inactivated vaccines can be given to patients on immunosuppression (as per Australian Standard Vaccination Schedule), whereas live vaccines need to be timed with therapy.
Malignancy screening
Patients on chronic immunosuppression must be up-to-date with their routine national screening programs.
Of note, women with IBD on immunosuppressive therapy need to ensure their CST has been done.
A recently published meta-analysis found sufficient evidence to suggest an increased risk of cervical high-grade dysplasia and cancer in patients with IBD on immunosuppressive medications.17
Patients with IBD should undergo screening for melanoma independent of the use of biologic therapy, whereas those on immunomodulators (6-MP or azathioprine) should undergo screening for non-melanoma squamous cell cancer (NMSC) particularly over the age of 50. Overall, IBD was associated with a 37% increase in risk of melanoma compared to the general population ( Singh et al 2014 ). There is a paucity of data regarding the evidence of NMSC in IBD patients, however in general those who are chronically immunosuppressed have an increased risk of SCCs and BCCs.18
Given these trends it is crucial that patients have at least annual skin surveillance and education regarding sun protection, including dermatology referral in those identified as higher risk.
Different parameters arise for colorectal cancer (CRC) screening in patients with IBD as per the Gastroenterological Society of Australia (GESA) guidelines which have been summarised in the tables on page 28.
Iron deficiency/nutrition
F or patients with mild disease or those in remission, this should be monitored every six months. Those with active disease should have iron stores and haemoglobin tested every three months. Serum folate and B12 should be measured annually.
Diagnostic criteria for iron deficiency varies for patients with IBD, as ferritin is influenced by the degree of inflammation. In patients without clinical, endoscopic or biochemical evidence of active disease, serum ferritin 50, or previous fragility fractures).
Psychological well-being
Anxiety and depression has not been shown to have any direct correlation with disease activity, however it certainly plays a role in treatment adherence and patient perspective which can subsequently impact disease trajectory. A systematic review found that anxiety was present in 19% of IBD patients vs 9.6% of the background population, and depression found in 21.2% vs 13.4%. There was just as much depression in those with inactive disease as those with active.23
In another Canadian study, researcers demonstrated that the interaction of perceived stress and avoidance coping were predictors of earlier relapse.24 Evidently, screening patients for mood disorders and offering early intervention can improve patient outcomes as well as overall quality of life.
Pregnancy and lactation
As per the ECCO guidelines, there is no evidence that ulcerative colitis or inactive Crohn’s disease affects fertility. The same applies for medications in females, while sulfasalazine causes reversible oligospermia. Pregnancy may influence the course of IBD, and it has been shown that conception at the time of active disease increases the risk of activity during pregnancy. This requires close coordination between the obstetrician and GP.
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Checkpoint Checkmate: Adverse Event Management for Checkpoint Inhibitors

<h1>Checkpoint Checkmate: Adverse Event Management for Checkpoint Inhibitors</h1>

Checkpoint Checkmate: Adverse Event Management for Checkpoint Inhibitors

Checkpoint Checkmate: Adverse Event Management for Checkpoint Inhibitors Healio Rheumatology, December 2018
Although it might seem silly to use the game Whack-A-Mole to illustrate a point about health care — knock one down and another pops up — this seems to be a fitting comparison when dealing with immune-related adverse events associated with the immune checkpoint inhibition therapies that are proliferating in cancer treatment.
While often touted as the next “game-changer” in cancer therapy, checkpoint inhibitors have also given rise to a whole new array of complications for the patient that appear to be rheumatic in origin, a development which has brought rheumatologists into this evolving field. Though, at present, these events appear to be relatively infrequent, their infrequency also makes them difficult to spot, particularly for oncologists not familiar with the particulars of rheumatology. Consequently, little is known about how severe these complications may be, and how they need to be managed. With seven checkpoint inhibitors currently approved for a number of malignancies, and more poised to gain approval in the coming months, the field of rheumatology could be faced with a substantial new patient population, and many more “moles” to whack.
Current FDA-approved agents include anti-CTLA-4, anti-PD-1 and anti-PD-L1 drugs, which may be used in many solid tumor malignancies including melanoma, Hodgkin lymphoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Merkel cell carcinoma, according to Cassandra Calabrese, DO, from the department of rheumatologic and immunologic disease at the Cleveland Clinic. Approvals are likely forthcoming for anti-OX40 and anti-TIM-3 monoclonal antibodies, as well as inhibitors of other immunologic checkpoints. Although the introduction of immune checkpoint inhibitors has been a significant boon to cancer therapy, the associated complications of immune-related adverse events highlight the need for ongoing collaboration between oncology and rheumatology specialties, Anne R. Bass, MD, and other experts noted. Source: Hospital for Special Surgery
“As one would imagine, with their increased use, more patients are going to develop immune-related adverse events (irAEs),” she told Healio Rheumatology. “A rheumatologist must be able to recognize rheumatic irAEs as a complication of checkpoint inhibitors and be aware that many clinical syndromes have been described, including inflammatory arthritis, polymyalgia rheumatica, sicca syndrome, myositis and others. We must do our best to keep up with this quickly growing field, as it has already presented many challenges.”
For Anne R. Bass, MD, from Hospital for Special Surgery and Weill Cornell Medicine, identifying and diagnosing these patients, particularly those with arthritis, is the most urgent clinical need. “We are just beginning to define these arthritides, because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.”
Underlying genetics and environmental exposures may also contribute to the heterogeneity in this population, according to Bass. “In our patients, around 20% or 25% present with what looks like rheumatoid arthritis, with both large joints and small joints affected,” she said, noting that only some of them are seropositive. “Another 20% have polymyalgia rheumatica, which causes achy shoulders and hips. Then there is a group who have a large joint arthritis, usually the knees, hips, wrists and/or shoulders. We don’t see this pattern of arthritis outside of the immunotherapy context.”
Beyond these manifestations, Bass said that there are reports of psoriatic arthritis, scleroderma and vasculitis, but they are rare. Myositis is relatively common whereas dermatomyositis and lupus — diseases that are driven by interferon — are very rare. Some patients may have a disease susceptibility that is unmasked by immunotherapy, whereas others may have an immunotherapy-specific condition. “There are just a lot of uncertainties right now.” Professional Guidelines
The good news is that the oncology community has made strides to begin understanding these complications. As reported earlier this year in the Journal of Clinical Oncology, the American Society of Clinical Oncology has released a clinical practice guideline on management of irAEs in patients receiving checkpoint inhibitor therapy. Based on a systematic review of publications on immune checkpoint inhibitor therapy from 2000 through 2017, a multidisciplinary, multiorganizational panel of experts provided detailed recommendations for organ-specific management for skin, gastrointestinal, lung, endocrine, musculoskeletal, renal, nervous system, hematologic, cardiovascular and ocular irAEs.
Clinicians treating patients with immune checkpoint inhibitors should consider suspending these treatments in favor of corticosteroids at the sign of grade 2 toxicity. Prednisone 1 to 2 mg/kg per day or methylprednisolone 1 to 2 mg/kg per day may be used when grade 3 toxicities occur. A 4- to 6-week tapering period is recommended for patients who are transitioned to corticosteroids. It is recommended that with the exception of manageable endocrinopathies, grade 4 toxicities should result in permanent discontinuation of checkpoint inhibitor therapy.
The important “take-home message” of the American Society of Clinical Oncology practice guidelines, for Maria E. Suarez-Almazor, MD, PhD, of the department of general internal medicine at The University of Texas MD Anderson Cancer Center, is awareness that these events may occur, and that they need to be addressed promptly. She added that it is time for other organizations to follow suit. “The American College of Rheumatology has been offering educational opportunities at the annual meeting to make rheumatologists aware that these guidelines, and others from oncology groups, exist,” she said. “However, not all doctors can go to the meeting, and although there are online resources, most of these are in oncology forums.”
Uma Thanarajasingam, MD, PhD, of the department of rheumatology at the Mayo Clinic, underscored the practical nature of raised awareness of the guidelines. “Community rheumatologists need to understand that there is a place they can turn for information about these events, whether it is the guidelines or other experts who are familiar with them,” she said.
This can then lead to basic interventions early in the course of irAEs, according to Bass. “What I have learned from caring for patients with immunotherapy-induced arthritis is that it often becomes chronic, so it is important to start early with steroid-sparing agents,”she said. By the Numbers
In what many experts are considering the first key data set in the field, Richter and colleagues retrospectively reviewed all patients from the database at the Mayo Clinic who underwent checkpoint inhibitor therapy over a recent 7-year period. Results published in Arthritis & Rheumatology demonstrated that among 1,293 eligible patients, 43 were clinically diagnosed with rheumatic irAEs. Inflammatory arthritis was reported in 2% of the cohort (n = 34), with myopathy reported in 10 patients, while 17 fell into the category of “other rheumatic syndromes,” according to the findings.
“We still lack strong epidemiologic data, but rheumatologic irAEs like inflammatory arthritis can be seen in up to 7% of patients treated with certain checkpoint inhibitors,” Laura C. Cappelli, MD, MHS, from the division of rheumatology at Johns Hopkins School of Medicine, told Healio Rheumatology. “Other rheumatologic irAEs like myositis occur in less than 1% of patients treated with checkpoint inhibitors.” Anne R. Bass
Other findings from Richter and colleagues showed that inflammatory arthritis was polyarticular in most cases, and that 76% of these patients required glucocorticoids.
“We are really just getting a handle on the epidemiology,” Bass said. “The problem is that we see these cases, but don’t always know the denominator.” Laura C. Cappelli
Bass noted that a systematic review of clinical trials by Cappelli and colleagues in Arthritis Care & Research, reported that arthritis may occur in 1% to 7% of patients treated with checkpoint inhibitors, while arthralgia rates may range from 7% to 43%. “My guesstimate, based on the available data we have, is that arthritis occurs in about 5% of patients treated with checkpoint inhibitors, and around 20% experience joint pain,” she said. “However, many of these cases are missed by oncologists for two reasons: one, because they don’t pay as much attention to joint pain as a rheumatologist would, and two, because steroids used for other adverse events masks joint pain.”
A key concern is that oncologists do not typically recognize the difference between arthritis, arthralgia and polymyalgia syndromes, according to Suarez-Almazor. “Reports vary greatly across trials, possibly because of differences in musculoskeletal adverse events characterizations,” she said.
In a presentation at the 2018 Congress of Clinical Rheumatology, Ami A. Shah, MD, MHS, of the Johns Hopkins University School of Medicine, suggested that inflammatory arthritis may develop in approximately 5% of patients treated with anti-PD1 therapy. She added that sicca, polymyalgia rheumatica, myositis, single-organ vasculitis, lupus nephritis, psoriasis and psoriatic arthritis have also occurred, along with reports of scleroderma.
“When we talk about these rheumatic syndromes, there are three primary presentations: arthritis/arthralgia, polymyalgia and myositis,” Suarez-Almazor said. “Myositis is obviously the scariest, because it is acute and can be life-threatening. Admittedly, myositis probably occurs in less than 1% of patients, but we are very concerned about it because patients can also develop myocarditis, a potentially fatal complication.”
“What is felt to be weakness from myositis may be the result of progressive intracranial metastasis, for example,” Calabrese added.
Other issues Suarez-Almazor encouraged rheumatologists to consider is whether the immunotherapy is given as adjuvant or a primary treatment, patient’s response to oncologic therapy and life expectancy, and whether there are other alternatives for oncologic treatment. “These drugs have not been widely used in patients with limited cancer yet, but that could change,” she said. “Also, new drugs and new combinations will likely come on board, so that will also change the landscape.” Making the Diagnosis
Calabrese outlined the varied challenges in making a diagnosis. “This is a very heterogeneous patient population, with many patients having received chemotherapy, radiation and/or surgery prior to checkpoint inhibitor therapy, and they may have progression of their tumor at the time of evaluation,” she said. “It is important to keep other etiologies on the differential when evaluating a patient for rheumatic irAEs.” Cassandra Calabrese
It is also important to note that the rheumatic irAEs described thus far frequently have atypical features compared to de novo disease, according to Calabrese. “For example, they may lack characteristic autoantibodies or require higher doses of prednisone than would be expected,” she said. “Also, unlike all other irAEs to date, rheumatic manifestations appear to be the only irAE with inflammation that persists, even despite discontinuation of the checkpoint inhibitor.”
This persistence of rheumatologic irAEs, even several years after checkpoint inhibitor therapy has been stopped, is another prominent concern for rheumatologists, according to Cappelli. “We have patients who are 3 years out from receiving immune checkpoint inhibitors who continue to have issues with inflammatory arthritis,” she said. However, she believes that diagnosis is improving. “It is still a problem for oncology and other nonrheumatology providers. There is a knowledge gap in the range of rheumatologic irAEs like polymyalgia rheumatica, myositis, vasculitis and inflammatory arthritis.”
Cappelli added that the musculoskeletal examination is not taught in depth in all medical training programs, making it difficult for providers to determine if joints are swollen, warm or have a decreased range of motion when evaluating for inflammatory arthritis. “In the area of myositis, sometimes routine labs will show an elevated aspartate aminotransferase, which can come from muscle in the setting of myositis, but clinicians may go down the path of investigating liver pathology,” she said.
For Suarez-Almazor, referral to a rheumatologist at the first sign of any such syndrome is critical. “Not only will a rheumatologist be able to make a diagnosis, but they will be familiar with the medications necessary to treat these patients,” she said. “We have seen that these syndromes are different from other immune-related arthritis in that they sometimes can have an insidious onset and can linger for weeks or months, even after discontinuing immunotherapy.” Treatment Complications
As with other aspects of these syndromes, many clinicians remain mostly in the dark about treatment complications. In their study in the Journal for ImmunoTherapy of Cancer, Moseley and colleagues conducted a retrospective case series for patients referred to endocrinology or rheumatology for bone disorders after treatment with therapies targeting PD-1, CTLA-4, or both. Though there were only six events overall, they suggested that it may portend skeletal adverse events of immune checkpoint therapy.
“The main challenge in managing patients with rheumatologic irAEs is the lack of evidence-based medicine to guide treatment,” Cappelli said. “IrAEs are a relatively new clinical issue and more research is needed to determine the most effective and safe treatments. The concern in treating irAEs is that immunosuppression may undermine the tumor immunologic response and have a negative impact on cancer progression.”
That said, Johnson and colleagues examined a cohort of 75 patients with immune-related enterocolitis who had undergone treatment with checkpoint inhibition. They hypothesized that the addition of infliximab (Remicade, Janssen) to front-line corticosteroid therapy may improve these events. Results published in the Journal for ImmunoTherapy of Cancer demonstrated that diarrhea resolved in 3 days among patients in the infliximab arm and 9 days among those treated only with corticosteroids ( P < .001). Time to steroid titration was also shorter in patients in the infliximab arm, 4 vs. 13 days ( P < .001).
Thanarajasingam offered a general point on treating these patients. “Rheumatologists understand better than oncologists how aggressive we can be,” she said. However, she echoed Cappelli’s point that evidence-based strategies are lacking, and that communication with other physicians is critical.
Additional findings from Richter and colleagues showed that the mean treatment duration was 18 weeks (SD = 18 weeks). Disease-modifying drugs were reported in 15% of their cohort, while 9% required discontinuation of immune checkpoint therapy. Nine patients required permanent discontinuation of immune checkpoint therapy after treatment of myopathy with glucocorticoids. They also found cases of connective tissue diseases, vasculitis, PMR-like syndrome and flared pre-existing rheumatic disease. Clinicians used immunosuppression in 71% of these cases. However, 12% required discontinuation of checkpoint inhibition. Uma Thanarajasingam
“Any time we go beyond prednisone, we have to partner with oncologists to see how much damage we might be doing to the immune system,” Thanarajasingam said. “We have to understand the status of the underlying cancer, whether the patient is responding really well to checkpoint inhibitor therapy even if they are having a great deal of arthritic pain. Sometimes we have to take a hiatus from the treatment we are using, or switch courses.”
Bass suggested that oncologists who deal with melanoma are more familiar with immune-related adverse events because they have been using immunotherapy the longest. “For my part, I try to understand the nature of the malignancy and its prognosis, and how immunosuppressive therapy may impact the patient,” she said. For example, she noted that Merkel cell carcinoma is immunologically-sensitive and occurs primarily in immune-suppressed individuals; treating immune-related adverse events in such a patient may be much less safe than in someone with melanoma. “You have to understand that the treatment approach for every patient and every tumor is different. I would love to be able to offer concrete recommendations that always apply. The key is to work together with the oncologist and the patient to discuss risks and benefits, and to learn from each other.”
A small but growing area of research deals with specific drug-drug interactions, according to Shah’s presentation. She suggested that currently available information indicates that corticosteroids and short-term TNF inhibitor use may be tolerable without affecting melanoma responses to both ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb).
“These interactions are still quite an unknown area,” Thanarajasingam said. “We get a sense that certain combinations may have more or less toxicity than others, and there are data emerging for ipilimumab and nivolumab, for example.”
When more malignancies are added to the mix, the difficulties are likely to be compounded, according to Thanarajasingam. “Obviously, because these drugs were first approved in melanoma, the toxicities reported in that type of cancer are greatest,” she said. “As usage expands, it will be interesting to see how the toxicity profile changes. For example, lymphoma is a completely different type of cancer, and the immune cells are part of the cancer, so what are the implications for adverse events? It’s still such a new area, so it’s hard to say.” Working Alongside Oncologists
Cappelli stressed basics when it comes to working with oncologists. “Communication is the most important thing to successfully care for patients with rheumatologic irAEs,” she said. “The oncologist and rheumatologist must reach consensus about ways to manage each patient.”
Even logistics are not to be taken lightly, according to Cappelli. “We contact the patient’s oncologist on the day of their clinic visit to us so we can confirm the plan,” she said. “It is also important for the patient to be aware of the role each physician plays in their care. Often patients ask us about plans for their cancer therapy and we need to remind them that their oncologist will guide their cancer treatment and we will manage their side effects, in collaboration with their oncologist.”
Calabrese stressed basics. “If there are symptoms of grade 2 or higher based on CTCAE grading, they should be referred to a rheumatologist,” she said. “Long-term management of these patients requires multidisciplinary care that addresses the patients’ rheumatic manifestations while at the same time treating their cancer.” Maria Suarez-Almazor
Management may need to involve other specialties, according to Suarez-Almazor. “We need to promptly recognize when others need to be involved, for instance cardiologists when suspecting myocarditis,” she said. “The benefits and harms of therapies need to be understood quickly, along with how the various therapies are interacting with each other.” Shifting the Field
There is no doubt that this patient population will change the field of rheumatology, according to Bass. The question is how much. “We have to take every opportunity to learn, because we are going to see more and more of these patients,” she said. “It is critical that we have people who understand and can manage these patients and the problems they confront.”
Bass believes that this also provides an opportunity to learn. “In most cases of RA, the development of antibodies to disease onset can usually be 3 to 5 years,” she said. “In immunotherapy patients, we are seeing arthritis develop within 3 to 4 months of starting treatment. This means we can study this disease and biomarkers over a shorter period of time, and they will likely teach us something about rheumatic diseases that we see in other contexts.”
Learning how to predict which patients receiving checkpoint inhibitors are prone to rheumatic complications will also allow researchers to study these events prospectively, Bass noted. “This may be a first step toward learning how to prevent arthritis, and could also be applied to the preclinical phases of RA.”
For Suarez-Almazor, having mechanisms in place to identify and manage these fast-developing patients is critical. “Many of these are patients who cannot wait to be seen by a rheumatologist for weeks or months, as decisions about their cancer treatment are critical,” she said.
“At this point, there are so many more questions than answers,” Calabrese said. “We have much to learn about risk factors, biomarkers, pathogenesis and optimal treatment of rheumatic irAEs, as well as the impact that treatment for irAEs may have on cancer outcomes. I am most interested in identifying risk factors for rheumatic irAEs and will be looking at autoimmune serology and family history prior to checkpoint inhibitor initiation and trying to see if we can identify serological biomarkers or other signs that a patient may be predisposed to developing a rheumatic irAE.”
Thanarajasingam is optimistic that the rheumatology community is responding appropriately. “Over the last two ACR meetings, the field went from a couple of posters at the back of the presentation hall to several talks in larger sessions,” she said. “We are reaching more people, including pharma, which is going into the community to let providers know that this is an issue.” – by Rob Volansky References: Brahmer JR, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.77.6385. Cappelli LC, et al. Arthritis Care Res. 2018;doi:10.1002/acr.23177. Johnson DH, et al. J Immunother Cancer. 2018;doi: 10.1186/s40425-018-0412-0. Kapiteijn E. Abstract SP0097. Presented at: EULAR Annual Congress; June 13-16, 2018; Amsterdam. Moseley KF, et al. J Immunother Cancer. 2018;doi: 10.1186/s40425-018-0417-8. Richter MD, et al. Arthritis Rheumatol. 2018;doi: 10.1002/art.40745. Shah A. Cancer, immunotherapy and autoimmune syndromes: Rheumatic consequences of checkpoint inhibitors; May 17-20, 2018; Destin, Fla. For more information: Anne R. Bass, MD, can be reached at 535 East 70th St., New York, NY 10021; email: . Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: . Laura C. Cappelli, MD, MHS, can be reached at 5501 Hopkins Bayview Circle, Suite 1B1, Baltimore, MD 21224; email: . Maria Suarez-Almazor, MD, PhD, can be reached at 1515 Holcombe Blvd. #437, Houston, TX 77030; email: . Uma Thanarajasingam, MD, PhD, can be reached at 200 First St. SW, Rochester, MN 55905; email: . Disclosures: Bass, Calabrese, Suarez-Almazor and Thanarajasingam report no relevant financial disclosures. Cappelli reports receiving research funding from Bristol-Myers Squibb, and consulting for Regeneron/Sanofi.
Although it might seem silly to use the game Whack-A-Mole to illustrate a point about health care — knock one down and another pops up — this seems to be a fitting comparison when dealing with immune-related adverse events associated with the immune checkpoint inhibition therapies that are proliferating in cancer treatment.
While often touted as the next “game-changer” in cancer therapy, checkpoint inhibitors have also given rise to a whole new array of complications for the patient that appear to be rheumatic in origin, a development which has brought rheumatologists into this evolving field. Though, at present, these events appear to be relatively infrequent, their infrequency also makes them difficult to spot, particularly for oncologists not familiar with the particulars of rheumatology. Consequently, little is known about how severe these complications may be, and how they need to be managed. With seven checkpoint inhibitors currently approved for a number of malignancies, and more poised to gain approval in the coming months, the field of rheumatology could be faced with a substantial new patient population, and many more “moles” to whack.
Current FDA-approved agents include anti-CTLA-4, anti-PD-1 and anti-PD-L1 drugs, which may be used in many solid tumor malignancies including melanoma, Hodgkin lymphoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Merkel cell carcinoma, according to Cassandra Calabrese, DO, from the department of rheumatologic and immunologic disease at the Cleveland Clinic. Approvals are likely forthcoming for anti-OX40 and anti-TIM-3 monoclonal antibodies, as well as inhibitors of other immunologic checkpoints. Although the introduction of immune checkpoint inhibitors has been a significant boon to cancer therapy, the associated complications of immune-related adverse events highlight the need for ongoing collaboration between oncology and rheumatology specialties, Anne R. Bass, MD, and other experts noted. Source: Hospital for Special Surgery
“As one would imagine, with their increased use, more patients are going to develop immune-related adverse events (irAEs),” she told Healio Rheumatology. “A rheumatologist must be able to recognize rheumatic irAEs as a complication of checkpoint inhibitors and be aware that many clinical syndromes have been described, including inflammatory arthritis, polymyalgia rheumatica, sicca syndrome, myositis and others. We must do our best to keep up with this quickly growing field, as it has already presented many challenges.”
For Anne R. Bass, MD, from Hospital for Special Surgery and Weill Cornell Medicine, identifying and diagnosing these patients, particularly those with arthritis, is the most urgent clinical need. “We are just beginning to define these arthritides, because they are so heterogeneous,” she said. “If you see five different patients, you might see five different phenotypes.”
Underlying genetics and environmental exposures may also contribute to the heterogeneity in this population, according to Bass. “In our patients, around 20% or 25% present with what looks like rheumatoid arthritis, with both large joints and small joints affected,” she said, noting that only some of them are seropositive. “Another 20% have polymyalgia rheumatica, which causes achy shoulders and hips. Then there is a group who have a large joint arthritis, usually the knees, hips, wrists and/or shoulders. We don’t see this pattern of arthritis outside of the immunotherapy context.”
Beyond these manifestations, Bass said that there are reports of psoriatic arthritis, scleroderma and vasculitis, but they are rare. Myositis is relatively common whereas dermatomyositis and lupus — diseases that are driven by interferon — are very rare. Some patients may have a disease susceptibility that is unmasked by immunotherapy, whereas others may have an immunotherapy-specific condition. “There are just a lot of uncertainties right now.” Professional Guidelines
The good news is that the oncology community has made strides to begin understanding these complications. As reported earlier this year in the Journal of Clinical Oncology, the American Society of Clinical Oncology has released a clinical practice guideline on management of irAEs in patients receiving checkpoint inhibitor therapy. Based on a systematic review of publications on immune checkpoint inhibitor therapy from 2000 through 2017, a multidisciplinary, multiorganizational panel of experts provided detailed recommendations for organ-specific management for skin, gastrointestinal, lung, endocrine, musculoskeletal, renal, nervous system, hematologic, cardiovascular and ocular irAEs.
Clinicians treating patients with immune checkpoint inhibitors should consider suspending these treatments in favor of corticosteroids at the sign of grade 2 toxicity. Prednisone 1 to 2 mg/kg per day or methylprednisolone 1 to 2 mg/kg per day may be used when grade 3 toxicities occur. A 4- to 6-week tapering period is recommended for patients who are transitioned to corticosteroids. It is recommended that with the exception of manageable endocrinopathies, grade 4 toxicities should result in permanent discontinuation of checkpoint inhibitor therapy. PAGE BREAK
The important “take-home message” of the American Society of Clinical Oncology practice guidelines, for Maria E. Suarez-Almazor, MD, PhD, of the department of general internal medicine at The University of Texas MD Anderson Cancer Center, is awareness that these events may occur, and that they need to be addressed promptly. She added that it is time for other organizations to follow suit. “The American College of Rheumatology has been offering educational opportunities at the annual meeting to make rheumatologists aware that these guidelines, and others from oncology groups, exist,” she said. “However, not all doctors can go to the meeting, and although there are online resources, most of these are in oncology forums.”
Uma Thanarajasingam, MD, PhD, of the department of rheumatology at the Mayo Clinic, underscored the practical nature of raised awareness of the guidelines. “Community rheumatologists need to understand that there is a place they can turn for information about these events, whether it is the guidelines or other experts who are familiar with them,” she said.
This can then lead to basic interventions early in the course of irAEs, according to Bass. “What I have learned from caring for patients with immunotherapy-induced arthritis is that it often becomes chronic, so it is important to start early with steroid-sparing agents,”she said. By the Numbers
In what many experts are considering the first key data set in the field, Richter and colleagues retrospectively reviewed all patients from the database at the Mayo Clinic who underwent checkpoint inhibitor therapy over a recent 7-year period. Results published in Arthritis & Rheumatology demonstrated that among 1,293 eligible patients, 43 were clinically diagnosed with rheumatic irAEs. Inflammatory arthritis was reported in 2% of the cohort (n = 34), with myopathy reported in 10 patients, while 17 fell into the category of “other rheumatic syndromes,” according to the findings.
“We still lack strong epidemiologic data, but rheumatologic irAEs like inflammatory arthritis can be seen in up to 7% of patients treated with certain checkpoint inhibitors,” Laura C. Cappelli, MD, MHS, from the division of rheumatology at Johns Hopkins School of Medicine, told Healio Rheumatology. “Other rheumatologic irAEs like myositis occur in less than 1% of patients treated with checkpoint inhibitors.” Anne R. Bass
Other findings from Richter and colleagues showed that inflammatory arthritis was polyarticular in most cases, and that 76% of these patients required glucocorticoids.
“We are really just getting a handle on the epidemiology,” Bass said. “The problem is that we see these cases, but don’t always know the denominator.” Laura C. Cappelli
Bass noted that a systematic review of clinical trials by Cappelli and colleagues in Arthritis Care & Research, reported that arthritis may occur in 1% to 7% of patients treated with checkpoint inhibitors, while arthralgia rates may range from 7% to 43%. “My guesstimate, based on the available data we have, is that arthritis occurs in about 5% of patients treated with checkpoint inhibitors, and around 20% experience joint pain,” she said. “However, many of these cases are missed by oncologists for two reasons: one, because they don’t pay as much attention to joint pain as a rheumatologist would, and two, because steroids used for other adverse events masks joint pain.”
A key concern is that oncologists do not typically recognize the difference between arthritis, arthralgia and polymyalgia syndromes, according to Suarez-Almazor. “Reports vary greatly across trials, possibly because of differences in musculoskeletal adverse events characterizations,” she said.
In a presentation at the 2018 Congress of Clinical Rheumatology, Ami A. Shah, MD, MHS, of the Johns Hopkins University School of Medicine, suggested that inflammatory arthritis may develop in approximately 5% of patients treated with anti-PD1 therapy. She added that sicca, polymyalgia rheumatica, myositis, single-organ vasculitis, lupus nephritis, psoriasis and psoriatic arthritis have also occurred, along with reports of scleroderma. PAGE BREAK
“When we talk about these rheumatic syndromes, there are three primary presentations: arthritis/arthralgia, polymyalgia and myositis,” Suarez-Almazor said. “Myositis is obviously the scariest, because it is acute and can be life-threatening. Admittedly, myositis probably occurs in less than 1% of patients, but we are very concerned about it because patients can also develop myocarditis, a potentially fatal complication.”
“What is felt to be weakness from myositis may be the result of progressive intracranial metastasis, for example,” Calabrese added.
Other issues Suarez-Almazor encouraged rheumatologists to consider is whether the immunotherapy is given as adjuvant or a primary treatment, patient’s response to oncologic therapy and life expectancy, and whether there are other alternatives for oncologic treatment. “These drugs have not been widely used in patients with limited cancer yet, but that could change,” she said. “Also, new drugs and new combinations will likely come on board, so that will also change the landscape.” Making the Diagnosis
Calabrese outlined the varied challenges in making a diagnosis. “This is a very heterogeneous patient population, with many patients having received chemotherapy, radiation and/or surgery prior to checkpoint inhibitor therapy, and they may have progression of their tumor at the time of evaluation,” she said. “It is important to keep other etiologies on the differential when evaluating a patient for rheumatic irAEs.” Cassandra Calabrese
It is also important to note that the rheumatic irAEs described thus far frequently have atypical features compared to de novo disease, according to Calabrese. “For example, they may lack characteristic autoantibodies or require higher doses of prednisone than would be expected,” she said. “Also, unlike all other irAEs to date, rheumatic manifestations appear to be the only irAE with inflammation that persists, even despite discontinuation of the checkpoint inhibitor.”
This persistence of rheumatologic irAEs, even several years after checkpoint inhibitor therapy has been stopped, is another prominent concern for rheumatologists, according to Cappelli. “We have patients who are 3 years out from receiving immune checkpoint inhibitors who continue to have issues with inflammatory arthritis,” she said. However, she believes that diagnosis is improving. “It is still a problem for oncology and other nonrheumatology providers. There is a knowledge gap in the range of rheumatologic irAEs like polymyalgia rheumatica, myositis, vasculitis and inflammatory arthritis.”
Cappelli added that the musculoskeletal examination is not taught in depth in all medical training programs, making it difficult for providers to determine if joints are swollen, warm or have a decreased range of motion when evaluating for inflammatory arthritis. “In the area of myositis, sometimes routine labs will show an elevated aspartate aminotransferase, which can come from muscle in the setting of myositis, but clinicians may go down the path of investigating liver pathology,” she said.
For Suarez-Almazor, referral to a rheumatologist at the first sign of any such syndrome is critical. “Not only will a rheumatologist be able to make a diagnosis, but they will be familiar with the medications necessary to treat these patients,” she said. “We have seen that these syndromes are different from other immune-related arthritis in that they sometimes can have an insidious onset and can linger for weeks or months, even after discontinuing immunotherapy.” Treatment Complications
As with other aspects of these syndromes, many clinicians remain mostly in the dark about treatment complications. In their study in the Journal for ImmunoTherapy of Cancer, Moseley and colleagues conducted a retrospective case series for patients referred to endocrinology or rheumatology for bone disorders after treatment with therapies targeting PD-1, CTLA-4, or both. Though there were only six events overall, they suggested that it may portend skeletal adverse events of immune checkpoint therapy. PAGE BREAK
“The main challenge in managing patients with rheumatologic irAEs is the lack of evidence-based medicine to guide treatment,” Cappelli said. “IrAEs are a relatively new clinical issue and more research is needed to determine the most effective and safe treatments. The concern in treating irAEs is that immunosuppression may undermine the tumor immunologic response and have a negative impact on cancer progression.”
That said, Johnson and colleagues examined a cohort of 75 patients with immune-related enterocolitis who had undergone treatment with checkpoint inhibition. They hypothesized that the addition of infliximab (Remicade, Janssen) to front-line corticosteroid therapy may improve these events. Results published in the Journal for ImmunoTherapy of Cancer demonstrated that diarrhea resolved in 3 days among patients in the infliximab arm and 9 days among those treated only with corticosteroids ( P < .001). Time to steroid titration was also shorter in patients in the infliximab arm, 4 vs. 13 days ( P < .001).
Thanarajasingam offered a general point on treating these patients. “Rheumatologists understand better than oncologists how aggressive we can be,” she said. However, she echoed Cappelli’s point that evidence-based strategies are lacking, and that communication with other physicians is critical.
Additional findings from Richter and colleagues showed that the mean treatment duration was 18 weeks (SD = 18 weeks). Disease-modifying drugs were reported in 15% of their cohort, while 9% required discontinuation of immune checkpoint therapy. Nine patients required permanent discontinuation of immune checkpoint therapy after treatment of myopathy with glucocorticoids. They also found cases of connective tissue diseases, vasculitis, PMR-like syndrome and flared pre-existing rheumatic disease. Clinicians used immunosuppression in 71% of these cases. However, 12% required discontinuation of checkpoint inhibition. Uma Thanarajasingam
“Any time we go beyond prednisone, we have to partner with oncologists to see how much damage we might be doing to the immune system,” Thanarajasingam said. “We have to understand the status of the underlying cancer, whether the patient is responding really well to checkpoint inhibitor therapy even if they are having a great deal of arthritic pain. Sometimes we have to take a hiatus from the treatment we are using, or switch courses.”
Bass suggested that oncologists who deal with melanoma are more familiar with immune-related adverse events because they have been using immunotherapy the longest. “For my part, I try to understand the nature of the malignancy and its prognosis, and how immunosuppressive therapy may impact the patient,” she said. For example, she noted that Merkel cell carcinoma is immunologically-sensitive and occurs primarily in immune-suppressed individuals; treating immune-related adverse events in such a patient may be much less safe than in someone with melanoma. “You have to understand that the treatment approach for every patient and every tumor is different. I would love to be able to offer concrete recommendations that always apply. The key is to work together with the oncologist and the patient to discuss risks and benefits, and to learn from each other.”
A small but growing area of research deals with specific drug-drug interactions, according to Shah’s presentation. She suggested that currently available information indicates that corticosteroids and short-term TNF inhibitor use may be tolerable without affecting melanoma responses to both ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb). PAGE BREAK
“These interactions are still quite an unknown area,” Thanarajasingam said. “We get a sense that certain combinations may have more or less toxicity than others, and there are data emerging for ipilimumab and nivolumab, for example.”
When more malignancies are added to the mix, the difficulties are likely to be compounded, according to Thanarajasingam. “Obviously, because these drugs were first approved in melanoma, the toxicities reported in that type of cancer are greatest,” she said. “As usage expands, it will be interesting to see how the toxicity profile changes. For example, lymphoma is a completely different type of cancer, and the immune cells are part of the cancer, so what are the implications for adverse events? It’s still such a new area, so it’s hard to say.” Working Alongside Oncologists
Cappelli stressed basics when it comes to working with oncologists. “Communication is the most important thing to successfully care for patients with rheumatologic irAEs,” she said. “The oncologist and rheumatologist must reach consensus about ways to manage each patient.”
Even logistics are not to be taken lightly, according to Cappelli. “We contact the patient’s oncologist on the day of their clinic visit to us so we can confirm the plan,” she said. “It is also important for the patient to be aware of the role each physician plays in their care. Often patients ask us about plans for their cancer therapy and we need to remind them that their oncologist will guide their cancer treatment and we will manage their side effects, in collaboration with their oncologist.”
Calabrese stressed basics. “If there are symptoms of grade 2 or higher based on CTCAE grading, they should be referred to a rheumatologist,” she said. “Long-term management of these patients requires multidisciplinary care that addresses the patients’ rheumatic manifestations while at the same time treating their cancer.” Maria Suarez-Almazor
Management may need to involve other specialties, according to Suarez-Almazor. “We need to promptly recognize when others need to be involved, for instance cardiologists when suspecting myocarditis,” she said. “The benefits and harms of therapies need to be understood quickly, along with how the various therapies are interacting with each other.” Shifting the Field
There is no doubt that this patient population will change the field of rheumatology, according to Bass. The question is how much. “We have to take every opportunity to learn, because we are going to see more and more of these patients,” she said. “It is critical that we have people who understand and can manage these patients and the problems they confront.”
Bass believes that this also provides an opportunity to learn. “In most cases of RA, the development of antibodies to disease onset can usually be 3 to 5 years,” she said. “In immunotherapy patients, we are seeing arthritis develop within 3 to 4 months of starting treatment. This means we can study this disease and biomarkers over a shorter period of time, and they will likely teach us something about rheumatic diseases that we see in other contexts.” PAGE BREAK
Learning how to predict which patients receiving checkpoint inhibitors are prone to rheumatic complications will also allow researchers to study these events prospectively, Bass noted. “This may be a first step toward learning how to prevent arthritis, and could also be applied to the preclinical phases of RA.”
For Suarez-Almazor, having mechanisms in place to identify and manage these fast-developing patients is critical. “Many of these are patients who cannot wait to be seen by a rheumatologist for weeks or months, as decisions about their cancer treatment are critical,” she said.
“At this point, there are so many more questions than answers,” Calabrese said. “We have much to learn about risk factors, biomarkers, pathogenesis and optimal treatment of rheumatic irAEs, as well as the impact that treatment for irAEs may have on cancer outcomes. I am most interested in identifying risk factors for rheumatic irAEs and will be looking at autoimmune serology and family history prior to checkpoint inhibitor initiation and trying to see if we can identify serological biomarkers or other signs that a patient may be predisposed to developing a rheumatic irAE.”
Thanarajasingam is optimistic that the rheumatology community is responding appropriately. “Over the last two ACR meetings, the field went from a couple of posters at the back of the presentation hall to several talks in larger sessions,” she said. “We are reaching more people, including pharma, which is going into the community to let providers know that this is an issue.” – by Rob Volansky References: Brahmer JR, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.77.6385. Cappelli LC, et al. Arthritis Care Res. 2018;doi:10.1002/acr.23177. Johnson DH, et al. J Immunother Cancer. 2018;doi: 10.1186/s40425-018-0412-0. Kapiteijn E. Abstract SP0097. Presented at: EULAR Annual Congress; June 13-16, 2018; Amsterdam. Moseley KF, et al. J Immunother Cancer. 2018;doi: 10.1186/s40425-018-0417-8. Richter MD, et al. Arthritis Rheumatol. 2018;doi: 10.1002/art.40745. Shah A. Cancer, immunotherapy and autoimmune syndromes: Rheumatic consequences of checkpoint inhibitors; May 17-20, 2018; Destin, Fla. For more information: Anne R. Bass, MD, can be reached at 535 East 70th St., New York, NY 10021; email: . Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: . Laura C. Cappelli, MD, MHS, can be reached at 5501 Hopkins Bayview Circle, Suite 1B1, Baltimore, MD 21224; email: . Maria Suarez-Almazor, MD, PhD, can be reached at 1515 Holcombe Blvd. #437, Houston, TX 77030; email: . Uma Thanarajasingam, MD, PhD, can be reached at 200 First St. SW, Rochester, MN 55905; email: . Disclosures: Bass, Calabrese, Suarez-Almazor and Thanarajasingam report no relevant financial disclosures. Cappelli reports receiving research funding from Bristol-Myers Squibb, and consulting for Regeneron/Sanofi. Read Next

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Pulmicort Flexhaler (Budesonide Inhalation Powder) – updated on RxList

<h1>Pulmicort Flexhaler (Budesonide Inhalation Powder) – updated on RxList</h1>

Pulmicort Flexhaler (Budesonide Inhalation Powder) – updated on RxList

68.2 Long-Term Safety in Patients 6 years of age and older
Non-placebo controlled long-term studies in children (at doses up to 360 mcg daily), and adolescent and adult subjects (at doses up to 720 mcg daily), treated for up to one year with PULMICORT FLEXHALER (budesonide inhalation powder) , revealed a similar pattern and incidence of adverse events. PULMICORT TURBUHALER; a different PULMICORT DPI
The following adverse reactions occurred in placebo-controlled clinical trials with similar or lower doses with inhaled budesonide via a different PULMICORT dry powder inhaler with an incidence of ≥ 1% in the budesonide group and were more common than in the placebo group:
≥ 1-3%: neck pain , syncope , abdominal pain , dry mouth, vomiting, weight gain, fracture, myalgia , hypertonia , migraine , ecchymosis , insomnia , infection, taste perversion, voice alteration.
Higher doses of inhaled budesonide (800 mcg twice daily) via a different PULMICORT dry powder inhaler resulted in an increased incidence of voice alteration, flu syndrome, dyspepsia , gastroenteritis, nausea, and back pain, compared with doses of 400 mcg twice daily.
asthenia , dyspepsia, arthralgia , cough increased, nausea and rhinitis .
: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema , bronchospasm, rash , contact dermatitis , urticaria , and cough, wheezing or bronchospasm in patients with severe milk protein hypersensitivity [see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS ]
: symptoms of hypocorticism and hypercorticism [see WARNINGS AND PRECAUTIONS ]
: cataracts, glaucoma, increased intraocular pressure [see WARNINGS AND PRECAUTIONS ]
: psychiatric symptoms including psychosis , depression , aggressive reactions, irritability, nervousness, restlessness, and anxiety
: throat irritation
: skin bruising
metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole , a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER (budesonide inhalation powder) with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin , indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see WARNINGS and PRECAUTIONS ]. & Precautions
PRECAUTIONS section.
pharynx with Candida albicans has occurred in patients treated with PULMICORT FLEXHALER. When such an infection develops, it should be treated with appropriate local or systemic (i.e. oral antifungal ) therapy while treatment with PULMICORT FLEXHALER continues, but at times, therapy with PULMICORT FLEXHALER (budesonide inhalation powder) may need to be interrupted. Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER.
hould be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with PULMICORT FLEXHALER (budesonide inhalation powder) . During such episodes, patients may require therapy with oral corticosteroids.
shortness of breath . When prescribing PULMICORT FLEXHALER, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g. albuterol ) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER (budesonide inhalation powder) .
contact dermatitis , urticaria , angioedema , and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur [see CONTRAINDICATIONS and ADVERSE REACTIONS ].
lactose , which contains trace levels of milk proteins. It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy . [see CONTRAINDICATIONS and ADVERSE REACTIONS , Post-marketing Experience ].
immune system are more susceptible to infection than healthy individuals. Chicken pox and measles , for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular ( IG ) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information .) If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.
leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with non-corticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections, or ocular simplex.
pituitary -adrenal (HPA) function.
prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.
trauma , surgery, or infection (particularly gastroenteritis ) or other conditions associated with severe electrolyte loss. Although PULMICORT FLEXHALER (budesonide inhalation powder) may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
ds of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
1 ] or morning peak expiratory flow [ PEF ]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude , weakness, nausea and vomiting, and hypotension .
rhinitis , conjunctivitis , eczema , arthritis , eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression ) despite maintenance or even improvement of respiratory function.
circulation and can be systemically active at higher doses, the beneficial effects of PULMICORT FLEXHALER (budesonide inhalation powder) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose . Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT FLEXHALER (budesonide inhalation powder) . Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT FLEXHALER should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
ects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of PULMICORT FLEXHALER should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
DRUG INTERACTIONS , CLINICAL PHARMACOLOGY ].
bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis , post menopausal status, tobacco use, advance age, poor nutrition , or chronic use of drugs that can reduce bone mass (e.g, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.
DOSAGE AND ADMINISTRATION , Use in Specific Populations ].
intraocular pressure , and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
y present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome , a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia , vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.
FDA Approved Patient Labeling .
Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e. oral) antifungal therapy while still continuing therapy with PULMICORT FLEXHALER (budesonide inhalation powder) , but at times therapy with PULMICORT FLEXHALER (budesonide inhalation powder) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised. [see WARNINGS AND PRECAUTIONS ]
WARNINGS AND PRECAUTIONS ]
CONTRAINDICATIONS , WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS ].
CONTRAINDICATIONS ].
immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS ]
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
HALER (budesonide inhalation powder) at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. If symptoms do not improve in that time frame or if the condition worsens, patients should be instructed to contact their physician.
sense the presence of any medication entering their lungs when inhaling from PULMICORT FLEXHALER (budesonide inhalation powder) . This lack of sensation does not mean that they did not get the medication. They should not repeat their inhalation even if they did not feel the medication when inhaling [see PATIENT INFORMATION ].
² basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.1 and 0.2 times, respectively, the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age, on a mcg/m² basis) and in female rats at oral doses up to 50 mc/kg (approximately 0.3 times the maximum recommended daily inhalation doses in adults and children 6 to 17 years of age, respectively, on a mcg/m² basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.3 times the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age, respectively, on a mcg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.3 times the maximum recommended daily inhalation doses in adults and children 6 to 17 years of age on a mcg/m² basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.
carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (approximately 0.6 and 0.7 times, respectively the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age on a mcg/m² basis).
Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive test in Drosophila melanogaster , and DNA repair analysis in rat hepatocyte culture.
subcutaneous doses up to 80 mcg/kg (approximately 0.5 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis).
² basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (approximately 0.03 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis).
prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period ), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively).
² basis and at a subcutaneous dose inrats that was approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m² basis.
physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations, Nursing Mothers ]. No studies have been conducted in breastfeeding women specifically with PULMICORT FLEXHALER; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar. PULMICORT FLEXHALER (budesonide inhalation powder) should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant. Dosing considerations include prescription or titration to the lowest clinically effective dose and use of PULMICORT FLEXHALER (budesonide inhalation powder) immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure. However, in general, PULMICORT FLEXHALER (budesonide inhalation powder) use should not delay or interfere with infant feeding.
Clinical Studies ]. Efficacy results in this age group were similar to those observed in patients 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older.
laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids including the impact on final adult height are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
osteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.
metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of inhaled budesonide on growth is not fully known.
DOSAGE AND ADMINISTRATION ].
ficacy between elderly and younger patients. Other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. & Contraindications
WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression ]. Another budesonide-containing dry powder inhaler at 3200 mcg daily administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.
² basis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 380 times the maximum recommended daily inhalation dose in adults and approximately 450 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m² basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m² basis) and less than 100 mg/kg in rats (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age based on a mcg/m² basis).
asymptomatic . The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism. WARNINGS AND PRECAUTIONS , DESCRIPTION ]. Mechanism of Action
Budesonide is an anti-inflammatory that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution
The activity of PULMICORT FLEXHALER (budesonide inhalation powder) is due to the parent drug, budesonide. In
The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine , eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of inhaled budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see ). Pharmacodynamics
To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered-dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the res
Inhaled budesonide has been shown to decrease airway reactivity in various challenge models, including histamine, methacholine, sodium metabisulfite, and monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.
Pre-treatment with inhaled budesonide 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (earlyphase reaction) and delayed (late-phase reaction) decrease in FEV following inhaled allergen challenge.
HPA Axis effects < 14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared with 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg of inhaled budesonide twice daily for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient taking doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of inhaled budesonide when administered at doses ranging from 100 to 800 mcg twice daily. In patients who had previously been oral steroid -dependent, use of inhaled budesonide at doses ranging from 100 to 800 mcg twice daily was associated with higher stimulated cortisol response compared with baseline following 1 year of therapy. Pharmacokinetics Absorption
After oral administration of budesonide, peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast, most of budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method and using a different budesonide containing dry-powder inhaler) with an absolute systemic availability of 39% of the metered dose. Peak steady-state plasma concentrations of budesonide delivered from PULMICORT FLEXHALER in adults with asthma (n=39) occurred at approximately 10 minutes post-dose and averaged 0.6 and 1.6 nmol/L at doses of 180 mcg once daily and 360 mcg twice daily, respectively.
In asthmatic patients, budesonide showed a linear increase in AUC and Cmax with increasing dose after both a single dose and repeated dosing of inhaled budesonide. Distribution
The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of PULMICORT FLEXHALER. Budesonide sh red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism
In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination
The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine. Special Populations
No clinically relevant pharmacokinetic differences have been identified due to race, sex, or advanced age. Geriatric
The pharmacokinetics of PULMICORT FLEXHALER (budesonide inhalation powder) in geriatric patients have not been specifically studied. Pediatric
Following intravenous dosing in pediatric patients age 10-14 years, plasma half-life was shorter than in adults (1.5 hours vs. 2.0 hours in adults). In the same population foll
Peak steady-state plasma concentrations of budesonide delivered via PULMICORT FLEXHALER in children and adolescents with asthma (n=14) occurred at approximately 15 to 30 minutes post-dose and averaged 0.4 and 1.5 nmol/L at doses of 180 mcg once daily and 360 mcg twice daily, respectively. Nursing Mothers
The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months . Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use In Specific Populations , Nursing Mothers ]. Renal or Hepatic Insufficiency
There are no data regarding the specific use of PULMICORT FLEXHALER (budesonide inhalation powder) in patients with hepatic or renal impairment. Redu Drug-Drug Interactions Inhibitors of cytochrome P450 enzymes
Ketoconazole WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS ].
Cimetidine cimetidine , a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide. Animal Toxicology Reproductive Toxicology Studies
As with other corticosteroids, budesonide was and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 mcg/kg (approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m² basis). Clinical Studies Asthma
The safety and efficacy of PULMICORT FLEXHALER (budesonide inhalation powder) were evaluated in two 12-week, double-blind, randomized, parallel-group, placebo-controlled clinical studies conducted at sites in the United States and Asia involving 1137 patients aged 6 to 80 years with mild to moderate asthma. Study 1 evaluated PULMICORT FLEXHALER (budesonide inhalation powder) 180 mcg, PULMICORT TURBUHALER 200 mcg, and placebo, each administered as 1 inhalation once daily or 2 inhalations twice daily in patients 18 years of age and older with mild to moderate asthma previously treated with inhaled corticosteroids. The delivered dose of PULMICORT FLEXHALER (budesonide inhalation powder) 180 mcg and PULMICORT TURBUHALER 200 mcg are the same; each delivers 160 mcg from the mouthpiece. Study 2 evaluated PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 2 inhalations once daily or 4 inhalations twice daily, PULMICORT TURBUHALER 200 mcg, 1 inhalation once daily or 2 inhalations twice daily, and placebo in pediatric patients aged 6 to 17 years with mild to moderate asthma. Both of the studies had a 2-week placebo treatment run-in period followed by a 12-week randomized treatment period. The primary endpoint was the difference between baseline and the mean of the treatment-period FEV (adults) or FEV 1 % predicted (children). Patients 18 years of age and older (Study 1)
This study enrolled 621 patients aged 18 to 80 years with mild-to-moderate asthma (mean baseline % predicted FEV 1 64.3%) whose symptoms were previously controlled on inhaled corticosteroids. Mean change from baseline in FEV 1 in the PULMICORT FLEXHALER (budesonide inhalation powder) 180 mcg, 2 inhalations twice-daily group was 0.28 liters, as compared to 0.10 liters in the placebo group (p < 0.001). Secondary endpoints of morning and evening peak expiratory flow rate, daytime asthma symptom severity, nighttime asthma symptom severity, daily rescue medication use, and the percentage of patients who met predefined asthma related withdrawal criteria showed differences from baseline favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001). 12-Week Trial in Adult Patients with Mild to Moderate Asthma (Study 1) Mean Change from Baseline in FEV (L) Patients 6 to 17 years of age (Study 2)
This study enrolled 516 patients aged 6 to 17 years with mild asthma (mean baseline % predicted FEV 84.9%). The study population included patients previously treated with inhaled corticosteroids for no more than 30 days before the study began (4%) and patients who were naïve to inhaled corticosteroids (96%). Mean change from baseline in % predicted FEV 1 during the 12-week treatment period in the PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 4 inhalations twice daily treatment group was 5.6 compared with 0.2 in the placebo group (p < 0.001). Secondary endpoints of morning and evening PEF showed differences from baseline favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001). 12-Week Trial in Pediatric Patients With Mild Asthma (Study 2) Mean Change from Baseline in Percent Predicted FEV

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Chemoradiotherapy With or Without Atezolizumab in Treating Patients With Localized Muscle Invasive Bladder Cancer

<h1>Chemoradiotherapy With or Without Atezolizumab in Treating Patients With Localized Muscle Invasive Bladder Cancer</h1>

Chemoradiotherapy With or Without Atezolizumab in Treating Patients With Localized Muscle Invasive Bladder Cancer

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Chemoradiotherapy With or Without Atezolizumab in Treating Patients With Localized Muscle Invasive Bladder Cancer The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT03775265 Recruitment Status : Not yet recruiting First Posted : December 13, 2018 Last Update Posted : December 13, 2018 Information provided by (Responsible Party): National Cancer Institute (NCI) Study Description Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: This phase III trial studies how well chemotherapy and radiation therapy work with or without atezolizumab in treating patients with localized muscle invasive bladder cancer. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as gemcitabine, cisplatin, fluorouracil and mitomycin-C, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with radiation therapy may kill more tumor cells. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving radiation therapy, chemotherapy, and atezolizumab may work better in treating patients with localized muscle invasive bladder cancer. Condition or disease Intervention/treatment Phase Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall Bladder Urothelial Carcinoma Stage II Bladder Cancer AJCC v8 Stage III Bladder Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8 Drug: Atezolizumab Drug: Cisplatin Drug: Fluorouracil Drug: Gemcitabine Drug: Mitomycin Other: Quality-of-Life Assessment Radiation: Radiation Therapy Other: Survey Administration Phase 3 Study Design Go to
Treatment Official Title: Phase III Randomized Trial of Concurrent Chemoradiotherapy With or Without Atezolizumab in Localized Muscle Invasive Bladder Cancer (Study SWOG/NRG 1806) Estimated Study Start Date : Arms and Interventions Go to
Intervention/treatment Active Comparator: Arm I (RT, chemotherapy) Patients undergo RT (3D CRT or IMRT) Monday-Friday for up to 7 weeks. Patients also receive chemotherapy based on physician’s choice of gemcitabine IV twice weekly for 6 weeks, or cisplatin IV weekly for 6 weeks concurrent with RT, or fluorouracil IV on same days as doses 1-5 and 16-20 of radiation therapy, and mitomycin IV on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. Drug: Cisplatin Other Name: Quality of Life Assessment Radiation: Radiation Therapy Ancillary studies Experimental: Arm II (RT, chemotherapy, atezolizumab) Patients undergo RT (3DCRT or IMRT) Monday-Friday for up to 7 weeks and receive chemotherapy based on physician’s choice as in Arm I. Patients also receive atezolizumab IV over 60 minutes on day 1 of chemotherapy. Treatment repeats every 21 days for a total of 6 months (9 doses total) in the absence of disease progression or unacceptable toxicity. Drug: Atezolizumab Other Name: Quality of Life Assessment Radiation: Radiation Therapy Outcome Measures Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Primary Outcome Measures : Bladder intact event-free survival (BI-EFS) [ Time Frame: From the date of randomization to the first documentation of a BI-EFS event, assessed up to 5 years ] At each time point, futility will be evaluated, and in the latter two analyses, efficacy will also be evaluated as specified. The final BI-EFS intent-to-treat analysis will be conducted using a stratified logrank test stratifying on stratification factors, and testing treatment at the one-sided significance level of 0.022 to account for multiple interim testing. The hazard ratio (HR) will be estimated using a stratified Cox proportional hazards model and the 95% confidence interval (CI) for the HR will be provided. Results from an unstratified analysis will also be provided. Kaplan-Meier methodology will be used to estimate the median BI-EFS for each treatment arm. Secondary Outcome Measures : Overall survival (OS) [ Time Frame: From date of randomization to death from any cause, assessed up to 5 years ] Will be estimated using Kaplan-Meier methodology for each treatment arm. Will be analyzed using a similar method as for BI-EFS. Modified BI-EFS (mBI-EFS) [ Time Frame: From date of randomization to the first documentation of a mBI-EFS event, assessed within 90 days ] Analysis of modified BI-EFS, i.e., a sensitivity analysis of BI-EFS, where bladder cancer event is defined as histologically proven presence of muscle invasive bladder cancer, clinical evidence of nodal or metastatic disease, radical cystectomy, or death within 90 days of receiving protocol specified treatment, will also be conducted. Biopsy response [ Time Frame: At 18 weeks ] The Cochran-Mantel-Haenszel statistic will be used with modified ridit scores to evaluate the biopsy outcomes of complete response versus (vs.) down-staging vs. no response for the two treatment arms. Complete response duration [ Time Frame: At 18 weeks ] For the subset of patients who achieve a complete response during the week 18 biopsy window, complete response duration is defined from the date of the biopsy documenting the complete response to the time of muscle invasive recurrence, local progression, evidence of metastatic disease or death due to any cause. Will be analyzed using a similar method as for BI-EFS. Progression-free survival [ Time Frame: From date of randomization to first radiologic or histologic evidence of local progression, nodal or distant metastasis, or death due to any cause, assessed up to 5 years ] Will be estimated using Kaplan-Meier methodology for each treatment arm. Will be analyzed using a similar method as for BI-EFS. Metastasis-free survival [ Time Frame: From date of randomization to first radiologic or histologic evidence of metastatic disease or death due to any cause, assessed up to 5 years ] Will be estimated using Kaplan-Meier methodology for each treatment arm. Will be analyzed using a similar method as for BI-EFS. Cancer-specific survival [ Time Frame: From date of randomization to date of death due to bladder cancer, assessed up to 5 years ] Quality of life [ Time Frame: Baseline up to 5 years ] Assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ)-C30. Will be examined using linear mixed models with patient considered as the random effect. The baseline physical function score and the stratification factors will be included in the regression model as adjustment covariates. Other Outcome Measures: Treatment interactions [ Time Frame: Up to 5 years ] A Cox regression model will be used to evaluate the main effects of treatment arm and the main effect for each stratification factor and the interaction of the stratification factor with treatment in terms of both the primary endpoint and secondary endpoints. The stratification factors to be evaluated include: (1) clinical stage T2 vs. T3/T4a, (2) intended chemotherapy regimen cisplatin vs. 5-FU + mitomycin-C vs. gemcitabine, (3) radiation field small pelvis vs. bladder only and (4) performance status 0-1 vs. 2. There may be other radiation summary measures that may also be explored in terms of their modification of the experimental treatment effect including extent of radiation to lymph node fields. Subgroup analysis defined by stratification factors will also be conducted for primary endpoint and key secondary. Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Inclusion Criteria: STEP 1 REGISTRATION: If this will be the first patient from a registering site to receive a given RT modality (3DCRT vs. IMRT), the site must first submit pre-RT planning documents within 3 days of Step 1 registration and receive approval from Imaging and Radiation Oncology Core (IROC) before randomizing the patient to Step 2. If this will not be the first patient to receive a specific RT modality, the patient should be immediately randomized to Step 2 on the same day. STEP 2 RANDOMIZATION If patient required review of pre-RT planning, randomization must occur within 14 days of initial registration. Patients must have histologically proven, T2-T4a N0M0 urothelial carcinoma of the bladder within 70 days prior to randomization. Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible. Patients with lymph nodes >= 1.0 cm in shortest cross-sectional diameter on imaging (computed tomography [CT]/magnetic resonance imaging [MRI]) must have a biopsy of the enlarged lymph node showing no tumor involvement within 70 days prior to randomization. These patients may be suitable for neoadjuvant chemotherapy and radical cystectomy and are eligible for this trial if they seek out a bladder sparing treatment strategy, however patients who have received prior systemic chemotherapy for bladder cancer are not eligible for the trial. Patients must undergo a transurethral resection of bladder tumor (TURBT) within 70 days prior to randomization. In a situation where a patient is referred from outside to the enrolling institution, patient must have a repeat cystoscopy by the urologist who will be following the patient on the clinical trial to assess the adequacy of the prior TURBT. Patient may then undergo repeat TURBT if deemed necessary as standard of care by the treating urologist. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection. Patient must not have T4b disease. Patients must undergo radiological staging within 70 days prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Patients must not have evidence of T4bN1-3 disease. Eligibility is based on the local radiology report. Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and kidney function meets criteria specified. Patients must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within the previous 24 months except Ta/T1/carcinoma in situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient had undergone complete nephroureterectomy. Patients must not have diffuse CIS based on cystoscopy and biopsy. Patient must be planning to receive one of the protocol specified chemotherapy regimens. All adverse events associated with any prior surgery and intravesical therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) grade =< 2 prior to randomization. Patient must not have received any systemic chemotherapy for their bladder cancer. Patient must not have had prior pelvic radiation. Patients must not have received prior treatment for muscle invasive bladder cancer including neoadjuvant chemotherapy for the current tumor. Patients must not have received any systemic therapy (including, but not limited to, interferon alfa-2b, high dose IL-2, pegylated interferon [PEG-IFN], anti-PD-1, anti-PD-L1), for non-muscle invasive bladder cancer. Prior intravesical BCG, interferon, and intravesical chemotherapy are allowed. Patients must not have received any of the following prohibited therapies within 28 days prior to randomization or be planning to receive any of the following prohibited therapies during protocol treatment: Anti-cancer systemic chemotherapy or biological therapy not specified in the protocol. Immunotherapy not specified in this protocol. Systemic or intravesical use of any non-study anti-cancer agent (investigational or non-investigational). Investigational agents other than atezolizumab. Live vaccines: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and are not allowed. Prior administration of intravesical BCG is allowed. Glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids (defined as 10 mg prednisone) are acceptable, however site investigators should consult with the study chair for any dose higher than 10 mg prednisone. Dexamethasone 4 mg iv with chemotherapy to prevent nausea is allowed. RANKL infusion: Concurrent denosumab (which binds the cytokine RANKL) for any known indication is prohibited due to interaction with study medication. Patients must not have a major surgical procedure within 28 days prior to randomization. If patient had any surgical procedure then they should have recovered to full presurgical performance status and surgical adverse events should have resolved to grade ==1,500/microliter (mcL) (within 28 days prior to randomization). Platelets >= 100,000/mcL (within 28 days prior to randomization). Hemoglobin >= 9 g/dL (within 28 days prior to randomization). Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 28 days prior to randomization). Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) = 25 mL/min. The creatinine used to calculate the clearance result must have been obtained within 28 days prior to randomization. Patients must have Zubrod performance status =< 2. Patients must have a baseline electrocardiography (ECG) performed within 30 days prior to randomization. Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis. Patients must not have an active infection requiring oral or IV antibiotics within 14 days prior to randomization. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are not eligible. If patient develops urinary tract infection after TURBT they must have recovered from the infection prior to registration. Patients must not have active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, Graves' disease treated with methimazole or glomerulonephritis. Patient must not have a history of active tuberculosis. If patient has a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV), they must meet the following criteria within 28 days prior to randomization. Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). Patients who are known to be positive for human immunodeficiency virus (HIV) are eligible only if they have all of the following: A stable regimen of highly active anti-retroviral therapy (HAART) No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests within 28 days prior to randomization. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for two years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible. Female patients of childbearing potential must have a serum pregnancy test prior to randomization. Patients must not be pregnant or nursing due to the potential teratogenic side effects of the protocol treatment. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of protocol treatment, and for 5 months (150 days) after the last dose of all study drugs. A woman is considered to be of "reproductive potential" if she has had a menses at any time in the preceding 12 consecutive months. Patients must not be known to be allergic to Chinese hamster egg or ovary cell products and must not have any known major allergic reactions to any study drug. Patients must be offered the opportunity to participate in specimen banking for future studies. Patients who can complete Patient-Reported Outcome instruments in English or Spanish must agree to complete the EORTC QLQ-C30, the EORTC QLQ-BLM30, the EPIC-26 (bowel domain only), and the EQ-5D-5L per protocol schedule of assessment. As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system. Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03775265 Sponsors and Collaborators

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My first experience with ER and Hospitals in US

My first experience with ER and Hospitals in US

Nov. 2018 has been the first time that I’ve ever visited Emergency Rooms (ER) and stayed in a hospital in US since I came to US in March 1997. Dealing with the doctors and navigating the Aetna insurance system has been a new experience. I decide to write the details down, for myself and my own interest.
First of all, I’ve selected my employer’s cheapest Aetna insurance plan (Plan 4 which is a High Deductible Health Plan (HDHP) and I need to pay the initial $1350 before the insurance would start to contribute. After $1350, I have to pay/share 20% coinsurance until I reach the annual maximum out-of-pocket $3500.
This HDHP has worked for me because I’ve not seen any doctor for about 3 years until now. This plan saves the following in monthly premium (in 2018) :
$159.98 (Plan 3) – $136.26 (Plan 4) = $23.72 per month → $284.64 per year $239.85 (Plan 1) – $136.26 (Plan 4) = $103.59 per month → $1243.08 per year And I get $500 from my employer in my Health Savings Account a year by joining this HDHP. Moreover, HDHP allows one to save around $3000 a year pre-tax (even avoiding the 6.2%/1.45% social-security/medicare taxes). So, roughly, one saves about another $1000 !
Therefore, compared to the most expensive plan (Plan 1) and the next cheapest plan (Plan 3), this HDHP allows me to save about ~$2743 and ~$1785 a year, if I don’t see any doctor at all in a year.
Of course, with my new experience in Nov. 2018 in which I visited two ER’s and stayed in 5 days in one hospital. I’ll try to see the effect later on.
I believe that I started to have headache the morning after I finished reading the novel “The President is Missing” sometime after 3 am on ~Nov. 1, 2018. I probably didn’t put too much attention to it at the beginning. Though I went to work every day, I came to home earlier than usual every day. I’d probably start to have more obvious headache in early afternoon (~2 pm) and it’s difficult for my eye to look at the computer screen. At night, it’s the most difficult when I tried to sleep. Since the brain and skull are forced to be placed on the pillow, the pressure and then the pain made it almost impossible to sleep. I tried eating CVS version of Tylenol (Acetaminophen) a couple times and it helped only for a short while.
On Nov. 11, 2018 (Sunday), I finally used the “Teladoc” (teladoc.com, something Aetna has always suggested)to do video-conferencing with a doctor using my smartphone. This cost $40. I felt that everything was in a hurry and I needed to describe my headache problem quickly. He quickly suggested that I did a CT scan and the easiest way was to go to the ER. Otherwise, I had to find my family doctor to prescribe CT scan and then I had to find a radiology center to do the CT scan. ( In fact, why couldn’t he prescribe a CT scan then ? ) Anyway, I waited until Nov. 12 (Monday) which was a holiday Veteran’s Day (for my Lab.). I tried to call my family doctor whom I haven’t seen for a couple years at least but he didn’t seem to have any available appointment until Wed. So, I decided to go to the ER at John T. Mather Memorial Hospital sometime after 9 am. I chose this hospital because
I was there to visit/help with a colleague about a year ago or so and I was familiar with it. The visitor’s parking is free, compared to Stony Brook University Hospital (SBUH). It’s the closest ER. That ER didn’t keep me wait for more than a few minutes before the people at “Triage” started to evaluate me with questions and vital measurements etc. (though I didn’t like the initial question of “Do you speak English ?” at the beginning). I soon got an EKG. Waiting a few minutes at the waiting room, I was carried by a wheelchair to do a CT scan for my brain, which was a quick and easy process. With some more blood tests, I was sent to a bed in a room with 3 other patients (partitioned by curtains).
They injected me with Benadryl (against allergy) and Reglan (against nausea/vomiting) in addition to saline. I shouldn’t have said “a little” when they asked me for any nausea symptom. An hour or so later, the attending doctor (Dr. Kim) doctor told me that CT scan didn’t find any internal bleeding or tumor etc. They then injected me with “toradol” (which Dr. Erika Newton in SBUH later commented that it’s like “ibuprofen”). I felt much better another hour or so later. They discharged me and I left the hospital at about 1 pm, with the prescription of “Fioricet” (for headache) and the unnecessary “Zofran” (for nausea/vomiting).
Cost: Dr. Eddie Kim and the J. Mather ER seem to want to charge $759 and $5205 respectively but Aetna only allows $334.96 (which I paid completely as it’s below the deductible) and $1564.2. But there is a 9.63% HCRA tax which makes the latter $1714.83. Obviously, the deductible $1350 is broken immediately and my total cost seem to be $334.96+$1095.78 = 1430.74 (as Aetna starts to contribute 80% and my portion is 20% only after the deductible is reached).
I felt good for a few hours but later at night, the fever and headache came back. I then took Fioricet and even added my own Acetaminophen in certain hours as I was not supposed to take Fioricet more than 3 times a day. I did this for about 3 days and though the pain-killers may reduce the headache/fever, I felt dizzy all day and didn’t feel that I was living. I felt that the brain/head was swollen at night (sometimes with fever — the highest that I measured was ~38.3 ℃). Putting the head on the pillow(s) has created pressure which made the pain even more unbearable. It’s probably the most serious right at the left eyebrows and the left temple, occasionally the center and at the lower part of the brain. But it’s always in the left brain. In any case, I started to drink some ginger tea after stopping using the pain-killers.
From aetna.com, the neurologist at the Mather Hospital referred to by Dr. Kim didn’t seem to be in the (in-network) list at aetna.com. ( Later on, I realized aetna.com may not list all the in-network doctors that should be listed and you may need to email/call to check to be sure. ) I made an appointment with a neurologist (in Stony Brook Medicine in 181 N. Belle Mead Road, Setauket) and got an appointment with a neurologist luckily (as initial response was 10 days later) on Nov. 16 (Friday) at 10 am. [ I initially called up the office a Stony Brook neurological surgeon as he was elected as the best neurologist in Long Island in 2015 but was quickly transferred. ] I saw Dr. Marchidann (Neurologist) and after a lot of evaluation, he didn’t have a solution and couldn’t prescribe anything at all. Of course, I could use pain-killer myself. The doctor did prescribed brain MRI/MRV (without contrast) and head MRA (with contrast) agreed to see each other on Nov. 20 (Tuesday) at 4 pm.
Cost: Dr. Marchidann’s office wants to charge $730 but Aetna only allows $380.44 and my 20% portion becomes $76.09.
Though the doctor suggested a bunch of radiological locations in Stony Brook and Setauket areas, I quickly learnt (by searching aetna.com and talking with them a bit) that not all locations were in-network for my Aetna network (“Choice POS II”). Apparently, Aetna likes to use “Zwanger-Pesiri Radiology” and there are a lot of them in Long Island. The quickest appointment that I could make with a “Zwanger-Pesiri” at Coram, a couple miles from my home on Nov. 20 at 1 pm.
Though at times, I was feeling that my headache would get better but it was an illusion. In the morning of Monday (Nov. 19), when I woke up, I suffered from ptosis of my left eyelid and the left eye seemed to be ~90% closed. If I used my finger to open my left eye, I could see and my eyeball could move and there was no double vision. Before that morning, my left eye could be open though I often chose to close it as I was a bit afraid too much light for that left eye. I almost wanted to go to an ER but I decided to do the MRI/MRV/MRA on the following day and fulfill the neurologist’s appointment first.
Nov. 20 @ 1 pm : The MRI/MRV/MRA experience was awful as I felt suffocated in the MRI chamber and I was told not to move. The horrible and very loud noise (apparently due to the rapid coil expansion in a fast magnetic field change) made one feel even worse. The earplugs helped (or headset in Stony Brook University Hospital) a bit only. As I investigated before, I could ask them to give me a CD for the images. I asked them and the technician told me that MRI pictures wer easy to get but somebody (in Stony Brook) remotely needed to get MRV/MRA picture for me which would take ~20 minutes. I did get a CD after about 20 minutes. On the face page of the CD, I saw only MRV/MRA mentioned but since I was not familiar, I thought MRI pictures might have been included anyway. I started to have bad feeling when I was looking at and backing up the images/software of the CD). When I saw Dr. Marchidann at 4 pm, he confirmed that there was no MRI images in the CD ! So, those Zwanger-Pesiri took so much time to make the MRV/MRA images and they forgot about the simple MRI images ! Of course, Zwanger-Pesiri has this “patient portal” page and you could see my MRI/MRV/MRA images on their websites.
When I asked Dr. Marchidann whether I should go to an ER, he suggested that I go to the one at Stony Brook University Hospital as it’s better This opinion must be a tiny bit biased
Cost: Dr. Marchidann’s office wants to charge $380 for that very short visit and Aetna only allows $199.18. My 20% responsibility becomes $39. 84.
Stony Brook University Hospital (SBUH) is bigger but there are even more patients. Arriving before 5 pm (after driving again with 1.1 eyes since Monday morning), I’ve needed to wait for at least for 30 minutes or even 45 minutes before the “Triage” staff of the ER started to evaluate me, though they did take vital measurements during the wait. I believe they put me to the Critical Care portion of the ER. I have had to wait about another one hour (and possibly more) before they sent me to a bed in a room to be examined.
Here came the attending doctor, Dr. Newton who turned out to be the wife of a USAtlas physicist in our Lab.’s Physics Dept. She started to flash many medical vocabularies while a younger guy (resident ?) was typing into his laptop. I later learnt (for example) the word “Ptosis” of my eyelids which I didn’t recognize when Dr. Marchidann started using it. I gave all my stories and the CD’s from Zwanger-Pesiri to Dr. Newton (which was the last time that I touched that CD as it’s never returned to me). The lack of MRI (but just MRV/MRA) has made them worry a bit and Dr. Newton wondered whether it’s this reason that Dr. Marchidann sent me to the ER. But I said that it should be mainly because the ptosis of my eyelid. But later on, a resident Neurologist seemed to be able to find a Zwanger-Pesiri report of that MRI scan from Dr. Marchidann’s system.
From the beginning, my fever has made them worry that there might be infection rather than just inflammation. They even measured my rectal temperature to be sure. Quite early on, they have explained to me that if it’s just “inflammation”, they would treat me with some sort of steroid but steroid would also suppress my immune system, which would be bad for me if I actually had infection. This “inflammation vs infection” issue has ultimately become the reason why I stayed in the Stony Brook University Hospital for 5 nights.
I stayed in this ER for about 24 hours and most of the time my bed was on the hall/corridor. As many as 6 neurologists have come to visit me, Dr. Kowalska tried to use dry ice to cold my left eyelid but nothing changed. She told me that I would need to stay in the Neurologist floor (13 th ) to allow them to eliminate the all kinds of infectious possibilities. Unfortunately, this move was much slower than I would have hoped for as there was no bed available on the 13 th floor. It was really a torture for my 24 hour stay in the ER. I felt hungry and have twice pleaded for food. What I got both times were turkey sandwich (too salty for me) with apple juice.
After midnight, Dr. Dickinson was the attending in the ER and he liked to speak some particle physics jokes with me once he knew that I was from Brookhaven National Laboratory. He and his resident doctor did a lumbar puncture in order to extract the cerebrospinal fluid. In addition to other infections, Dr. Dickinson was keen in the possibility of lyme disease as it’s quite popular in my Lab. The operation turned out to essentially painless. Probably a resident doctor tried twice and failed. At the end, Dr. Dickinson tried his hand and succeeded.
After that, SBUH did a MRI (with contrast) on my brain and CT scan (angiogram) on my head and neck (with contrast). Otherwise, I waited and waited. Another neurologist came and told me that my move to should be “soon” which turned out another 3 hours or so. This was the first time a doctor mentioned that what I had might be “Tolosa Hunt Syndrome” or generally “orbital pseudotumor”. I realized later that these names first appeared in those reports of CT scans and MRI.
After about 24 hours in the ER, around 4 pm or so on Nov. 21 (Wed.), I was finally taken to the 13 th floor which was probably the “highlight” of the 5 night hospital stay. Because I was sent to a single room and the view from the 13 th floor is quite magnificent. Furthermore, after just about 10 or 15 minutes after I got there, a young woman ophthalmologist came to check on my eye with all her two boxes of equipment. Every doctor asked me where I travelled outside USA last and I told them Machu Picchu (at the end of April and at the beginning of May). All of them had no more comments and Dr. Kowalska didn’t even know that it was in Peru (and her younger neurologist colleague had to tell her). But this ophthalmologist told me that she had been there 5 years ago. Then, we shared the same feeling of suffering from altitude sickness at Cusco but felt much stronger (“like superman” being the words that I used) when we reached Machu Picchu which is about 1000 m lower. Before she could finish, two infectious disease doctors arrived and they asked me even more questions about possible infections. Dr. Donelan’s last question was what novel I read that night/morning on Nov. 1
Around the midnight, a woman came to my room to take a X-ray on my chest which I heard later that they found a small black mark. They did another CT scan on my chest as well as abdomen and pelvis on Thursday (Nov. 22).
But the most miraculous thing happened in the morning of Thursday when I woke up. I found that I could open almost 50% of my eyes normally. The doctors (the resident or attending) or nurses all did the eye test again to see whether both my eyeballs could see up and down, left and right, just like before. They did so many times in the 5 days (tens of times) that I think I could perform the same test on anybody now. Apparently, my eyeballs seemed to function normally, without double vision.
The fever also seemed to disappear. The infection vs inflammation started to favor the inflammation. It’s a Thanksgiving Day and I don’t remember whether the attending doctor showed up that day. All other attending doctors in Stony Brook University Hospitals who have seen me have sent their bills to me (through Aetna) and there was no such charge on that day. I now conclude that the attending doctor didn’t show up on that day. Though I pleaded them to have some treatment, there was no decision and I was still eating only my usual B12 vitamin (something that I did every day at home).
24 hours after staying in a single room, my luck ran out and I was moved to a double room, sharing with it with an old gentleman who was often with his family members.
Two pulmonary doctors came to see me on Friday if I remember it correctly (as I think they probably didn’t come on the Thanksgiving Day). First came the resident and then the resident doctor came with the attending Dr. Patel which looks chic and seems to be someone who gives the most eloquent speech among the tens of doctors that I have seen in this Stony Brook University Hospital. They told me that the CT scan further identified a 1.1 cm nodule which they told me to deal with it in an outpatient manner after I left the hospital. Paraphrasing their words, they didn’t honestly think that this had anything to do with ptosis of eyelids or headache. At the hospital, since they didn’t have PET scan, the only thing to do was a biopsy but the two pulmonary experts didn’t recommend that. They said that they’d call me next week (presumably after I leave the hospital) to make a appointment to look at this in our outpatient clinic. A Pet scan can determine whether that nodule is active or not.
On the same Friday, there was an old gentleman technician who came to do a EMG test on me. This was ordered before but there was no personnel available to do so on Thanksgiving Day. As the technician said, this was probably to eliminate a remote possibility of any nerve problem. He did 3 sets of my test on my cheek, neck and wrist. Each time, he was using electricity of >400 V and a few mA to shock me. I didn’t enjoy it at all and this could be counted as the most torturous experience though the time duration was not too long (a second to a few seconds). The technician seemed to think that it’s not necessary to go on any more after the 3 sets as I was too responsive
On Friday, my eye opened even bigger from my own observation and that of the nurse who saw me for two consecutive days. The nurses took my temperature, pulse, blood pressure etc every 4 hours. It seems that my fever has gone. Headache seems to have disappeared (at least nothing like anything I have had in the first half of Novemeber).
By chance, I saw the face of the SBUH’s Friday’s attending doctor in Neurology, Dr. Schwartz as he shared the same outpatient clinic with Dr. Marchidann and I just heard about him from my old colleague a few days ago. My old/former colleague who is now >80 years ago apparently had Pakinson’s disease. Dr. Schwartz gave him some medicine to treat and somehow those medicine was completely useless. My colleague complained and Dr. Schwartz said that my colleague doesn’t have Pakinson’s disease and my colleague was just getting old. My colleague was not very pleased and was looking for another doctor and he called me to ask me to find the telephone no. of that doctor (due to some computer problem of his).
In spite of my improvement, Dr. Schwartz was not “brave enough” to make any call in the “infection vs inflammation” judgement, even though the resident doctor tried to persuade him a bit that infection was very unlikely (and the infectious department also hinted at that but they couldn’t swear on it). The resident doctor claimed that she might have seen one temperature measurement of 37.2 ℃ in the last 48 hours and it seems to me (very objectively of course) that this one measurement has persuaded Dr. Schwartz not to make his call. Dr. Schwartz also talked about fungal disease etc. He understood my desire for steroid treatment and repeated that if it was infectious, I could lose my eye. At the end, he told me that in US (and actually probably many other places in the world !), if I am sane, I could sign a letter to leave the hospital in spite of the doctor’s objection. He persuaded me to stay as any tests would be slow.
I was very disappointed as this was the 3 rd day already and I got better only by myself (and by the nurses or the food in SBUH) and there was NO treatement whatsoever. I had mentioned to them my upcoming foreign trip and I had strong desire to leave.
Every day the resident and/or attending doctors may be different and so are the nurses. Information transfer is never 100%. It’s not difficult to notice some inefficiency. Though the spinal fluid has been extracted on the first day, only some tests were initially done and they later realized that some other tests should have been done. The result of that only came after I left the hospital. I can check the results via the Stony Brook Medicine’s patient portal online, which is nice.
In the ~5 days that I was in the hospital, they have drawn tens of blood from me. I have seen phlebotomists, nurses and nursing assistants drawing bloods from me. It has become difficult at times (esp. for one nurse and one nursing assistant when they need many tubes) as they couldn’t find a good vein and the blood just only came very slowly like in drips. Of course, I didn’t enjoy any of these myself
Each morning, I asked the nurses to let me talk to the doctor as soon as possible. Fortunately, on Sat. morning, it’s a different attending doctor and probably a more senior/experienced one. Out from the beginning, Dr. Coyle seemed to discuss with me about releasing me from the hospital. I pleaded her for some treatment. Though she doubted how much useful data they’d get (a funny word ?! … but this may subconsciously reveal that they view me as some experimental object) as I had apparently recovered myself and it’s difficult to know how much effect the medicine was. Nevertheless, I told them I have read from Wikipedia that “corticosteroids should be continued on a tapering basis to avoid breakthrough inflammation” — of course I didn’t memorize those words but I just paraphrased. Dr. Coyle finally agreed to give me some low dose of steroid (which turned out to be 60 mg of Prednisone) and planned that I leave the hospital on Sunday. I told her that “she is the nicest person” in the world (to me) at that moment
Nothing bad has happened in the next 24 hours. I actually ventured out of the 13 th floor a couple times to buy a parking permit. Basically, it’s $10 a day in the Stony Brook University Visitors’ parking lot (after 3 hours). 5 days would cost $50. When I first asked whether there was a way to save some money. Nobody really knew and they sent a “social worker” kind of guy to me eventually (when I was still in the ER). He didn’t know much either and he said that he’d pass a telephone no. to me. I already google-d the no. and talked to the parking garage when he actually gave me a no. in a hour or two. There was a $35 monthly permit for visitors (which one could buy even just before you leave the hospital in spite of what the social worker or other people wrongly implied). The first step was to get a “blue stamp” from the Hospital’s “front desk” and nobody in the ER or the 13 th floor knew about this “blue stamp”. Talking a few times with the parking garage and I realized that it’s just a stupid thing that the front desk would give you once you told them that you needed to buy a visitor’s parking permit.
My first effort of leaving the 13 th floor failed as a nurse caught me and said that I shouldn’t leave the floor. She asked me why I wanted to leave and I told him of the parking permit business. A few minutes later, she came to my room and told me that after checking some regulations, though she didn’t allow me to leave, she couldn’t prevent me from leaving. So, if I wanted to go, I should just go. I went to the front desk Sat. morning and talked to a young girl there who seemed to be ignorant of it. Fortunately, a more senior colleague knew and “created” the blue stamp as shown in the picture
I needed to do this on Sat. because the parking garage office only opened from 11 am the following day (Sunday) and I figured that they would have let me go before 11 am. In the afternoon (as the parking office opened at 1 pm on Sat.), the lone staff in the parking garage found that I already owned a Stony Brook University “faculty/staff” parking permit (which is not useful for the Hospital’s visitor parking lot) and he couldn’t sell that visitor’s permit to me ( as I was not just a visitor) ! Fortunately, after some struggle, he found the “Parking Lot A and weekend hospital” monthly permit which cost $30. I shrugged and accepted as he said it’d work as long as I leave on Sunday It has saved me $20, more than I had planned. ( Though this is small compared to the entire medical expenses, I was happy to save $20, rather than lying on bed or doing nothing on the 13 th floor. )
So, on Sunday (Nov. 25, 2018), it’s evident that the steroid has not killed me and I was probably just better. The resident doctor of Neurology of that day came to see me first (who turned out to be the also the first Neurologist who came to see me on Tuesday night on Nov. 20) and he told me that they treated my problem as “Tolosa Hunt Syndrome”. He’s just waited for the blessing of the attending doctor to release me from the hospital. Then, half an hour or more later, Dr. Coyle came with the resident doctor and they told me that they’d release me formally immediately. They gave me prescription of Prednisone, starting from 60 mg to be decreased by 10 mg every 3 days. Then, the nurse needed to make up the paperwork and asked me to sign a couple times. All the nurses on the 13 th floor have been very nice. I remember Meghan (who was in the last couple of weeks for her 3-month practice and could practise alone afterwards) in particular because she dealt with me for 2 days (when both of my eyes could be opened) and was the one who actually released me on Sunday. Though she’s very young, from how she dealt with the patient in the next bed, she’s been very skillful and adept in dealing with constantly grumbling and demanding patient.
At this moment, I am still not sure whether I have received all the bills (as they have kept coming slowly and it’s difficult to tell whether it has come to an end). Though small compared to the SBUH’s hospital bill (nearly $60000), here I list all fees the “attending doctors” (in the SBUH whom I have talked to) have billed and the fees the Aetna insurance allows:
Bill Allowed by
insurance
Dr. Newton (ER) $590.00 $335.41
Dr. Dickinson (ER/Spinal Fluid Tap) $490.00 $303.41
Dr. Kowalska (Neurologist) $480.00 $249.03
Dr. Donelan (Infectious) $375.00 $298.83
Dr. Patel (Lung) $455.00 $360.90
Dr. Schwartz (Neurologist) $250.00 $130.21
Dr. Coyle (Neurologist) $255.00 $130.88
This list doesn’t include those attending doctors who have written the reports on CT and MRI scans. I don’t know how Aetna comes up with the figures (to the cents) and it’s different for each of the attending doctors. ( Did the doctor need to say how many minutes that they had talked with me ?? Or … )
To check the calculations, I have made up my own spreadsheet (which everyone may check). The single largest item is expectedly the one from the SBUH (in addition to the above list of fees from the attending doctors). They wanted to charge $59923.90 (not including tax) whereas Aetna’s allowed $9635.71 and it’s $10563.63 including the New York State’s HCRA tax. Consequently, I’ve reached the $3500, the maximum out-of-pocket for both “medical and prescription drugs”, which should be what I need to pay no matter how many more doctors I am going to see. There is an incentive for me to see doctors before Dec. 31, 2018 as it’s free for me
In the spreadsheet, I tried to estimate how much I would need to pay if I had had Plan 3 and Plan 1. For Plan 3, it’s clear that I’d pay $2000 plus the prescription cost as Plan 3 had maximum out-of-pocket for medical and prescription drugs separately. For Plan 1, I am not sure whether $500 would really cover all the “Inpatient Hospital” charge. How about the attending doctors and the scans which seemed to be charged separately ? In my spreadsheet, I assume the attending doctors are included in the $500 (for Plan 1) whereas the scans are not, just as a “compromised” calculation. It doesn’t make too much difference anyway, one way or another.
In any case, compared to $3500 that I need to pay for Plan 4, Plan 1 and Plan 3 would have saved me $1828.26 and $1468.26 respectively, which are less than the “differential” cost that I have gained by using Plan 4, ~$2743 and ~$1785, as stated at the top of the blog.
Therefore, the conclusion seems that I should stay in Plan 4 (even when I am sick) anyway !?
For $3500, I’ve had my first real and substantial spending in US’ medical facilities. I have been less than impressed. Maybe, it’s just the limit of modern medicine. The money spent is essentially all on the investigation and I recovered myself without treatment. ( I begged/argued for steroid at the end. )

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Medication Summary
Therapy with corticosteroids—such as the glucocorticoid prednisone—is often initially prescribed. An immunosuppressive agent is also sometimes initiated, either later or simultaneously; this is particularly the case in patients for whom high-dose, long-term therapy is anticipated. Some physicians select cyclosporine as the initial therapy. Other immunosuppressives used in treatment include azathioprine, mycophenolate, cyclophosphamide, chlorambucil, and tacrolimus.
The TNF inhibitors—which include thalidomide, etanercept, infliximab, adalimumab, and clofazimine—are showing promise in the treatment of pyoderma gangrenosum.
Corticosteroids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body’s immune response to diverse stimuli.
View full drug information
Prednisone
Prednisone is considered the drug of choice. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Methylprednisolone IV may be used in some patients.
Immunosuppressants
Class Summary
These agents have immunomodulatory effects. Also, see the clinical guideline summary from the Guidelines for prescribing azathioprine in dermatology, from the British Association of Dermatologists.
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Cyclosporine (Sandimmune, Neoral, Gengraf)
Cyclosporine has been demonstrated to be helpful in a variety of skin disorders. An effective steroid-sparing agent, it has also been used as primary therapy in some patients.
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Azathioprine (Imuran, Azasan)
Azathioprine is another drug that may be effective as a steroid-sparing agent. It antagonizes purine metabolism and inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Azathioprine may decrease the proliferation of immune cells, which results in lower autoimmune activity.
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Mycophenolate (CellCept, Myfortic)
Mycophenolate inhibits purine synthesis and the proliferation of human lymphocytes. It may be used as a steroid-sparing agent or as a primary agent in patients who do not respond to first-line agents.
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Cyclophosphamide
Cyclophosphamide is an alkylating agent that depresses B-cell and T-cell function. It is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.
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Chlorambucil (Leukeran)
Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription. It is used as a primary or steroid-sparing agent.
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Tacrolimus (Prograf, Hecoria)
Tacrolimus suppresses humoral immunity (T-lymphocyte) activity.
Blood Components
Class Summary
These agents are used to improve the clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.
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IV immunoglobulins (Octagam, Hizentra, Gammagard, Gamunex)
IV immunoglobulin neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon (INF)-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; and promotes remyelination. It may increase cerebrospinal fluid (CSF) IgG (10%).
Immunomodulators
Class Summary
These agents have effects on the activity of the immune system.
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Thalidomide (Thalomid)
Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration. In patients less than 50 kg (110 lb), start at the low end of the dose regimen.
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Ustekinumab (Stelara)
Ustekinumab is a human monoclonal antibody directed against IL-12 and IL-23, thereby interfering with T-cell differentiation and activation and subsequent cytokine cascades. It is indicated for moderate-to-severe plaque psoriasis and has been used successfully in pyoderma gangrenosum.
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Etanercept (Enbrel)
Etanercept is a soluble p75 TNF-receptor fusion protein (sTNFR-Ig). It inhibits TNF binding to cell surface receptors, thereby decreasing inflammatory and immune responses.
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Infliximab (Remicade)
Infliximab is a chimeric IgG1k monoclonal antibody that neutralizes the cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. The drug reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas.
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Adalimumab (Humira)
Adalimumab is a TNF-alpha inhibitor. It is a fully human inhibitor of TNF-alpha that is administered by subcutaneous (SC) injection.
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Clofazimine (Lamprene)
Clofazimine inhibits mycobacterial growth, binding preferentially to mycobacterial DNA. It has antimicrobial properties, but its mechanism of action is unknown.

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I lived on a high daily dose of Prednisone initial 400mg a day for a week, then tapered to 80mg a day for almost a year, then weaned 100% over 2 and a half months.
It was no picnic, but I will attest to the ability of it to help put a can of whoop-ass in side and make you the Hulk inside, while David Banner becomes a 16 year old girl on the outside.
I also have become “anti-biotic tolerant” (well, the bugs what get me, are given “free-fire ROE” against me due to over-prescribed in my youth), and that left me with an over reactive immune system that goes off scale if I get sick. (here comes the irony)I rarely get sick, but/and when I do, I get really bad sick, and my body goes apeshit crazy reacting and fighting it.
I think, that what happens is I kick the puny stuff to the side, no sniffle, no “low grade fevers” nothing for years, then “wham”, the mega monster bug hits me and my body reacts to try and kill it, but brings the burn Danger Close and then it starts losing ground, and I always end up needing steroids and the double antibiotic treatments like Augmentin and other 2 punch antibiotics.
Last two times I have been sick were once in 2005 (the big one) and once in 2012 (the flu, and my brain did the “12 Monkeys” trip, went on a bug hunt and left my body behind for almost 4 days, that left me with Hotel California memories).
So, before you dismiss with wave of hand, the ability of the drugs used, remember, that badass you became on the outside when demanding implements of destruction without a second thought to the mayhem you could produce, that was the whiny 16 year old, and the “Hulk” was one the inside showing all the “Loki” germs and shits what a puny god looks like when in the Swiffer mode.
Hope you get all better and stay gooder longer!

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