Alan E. Beer Center for Reproductive Immunology Patient Guidebook Updated May 4, 2011 15151 National Avenue #2 Los Gatos, CA 95032 USA Ph: 408-356-9500 Fax: 408-356-9509 1 Table of Contents Section I: Testing (page 3) Inherited Thrombophilia Antiphospholipid and antinuclear antibodies Leukocyte Antibody Detection Assay (LAD) Natural Killer cell assay Th1Th2 Assay T regulatory cell assay Endometrial biopsy Section II: Treatments A. Anticoagulants (page 6) Heparin Lovenox®/Clexane® Arixtra® B. Low dose aspirin (page 10) C. Metformin (page 11) D. Levothyroxin sodium (page 12) E. Dexamethasone/Prednisone (page 13) F. TNF-alpha inhibitors (Humira®/ Enbrel®/Simponi®) (page 15) G. Intravenous Immunoglobulin G (IVIG) (page 17) H. Intralipids (page 19) 2 Section I. Testing Introduction In your initial work-up, you will need to have blood tests. All requisitions and shipping information will be supplied to you after your chart has been reviewed. These tests will help your physician determine which therapies are best suited for you. Not only is it important to perform these tests prior to developing a treatment plan, it may also be important to repeat some of the tests during and following therapy to assure the physician that the therapy has been effective. Inherited Thrombophilia It is useful to consider tests that determine genetic tendencies related to blood coagulation. Clotting risk factors can negatively influence fertility and pregnancy outcome. A number of these factors are routinely assessed in the initial blood-testing panel. Examples of such tests include Factor V Leiden mutation, MTHFR A and C mutations, prothrombin mutation and PAI-1 mutation. These tests only need to be performed a single time as results do not change. For more information, click: Thrombophilia. Antiphospholipid antibodies (APA) and Antinuclear Antibodies (ANA) A second group of factors that need to be assessed are antibodies to natural substances in the body. Some of these are directed against fatty substances known as phospholipids. The presence of any one of the antiphospholipid antibodies suggests an increased proclivity toward coagulation. Because individuals produce these antibodies at varying levels during their lives and, in particular, at varying times during the reproductive cycle, your physician may wish to repeat testing for them. Antibodies can also be directed against other natural body substances such nuclear components. For more information about these autoantibodies, click: Antiphospholipid Antibodies and Antinuclear Antibodies (ANA). Leukocyte Antibody Detection Assay (LAD) Important amongst antibodies are ones that are directed not against your own body tissues but rather toward unique substances found in your partner distinct from your own. Remember the growing baby within the uterus bares your unique markings as well as those of its own. It is important that your immune system recognizes the non-self (allo) antigens to prepare it for pregnancy. A test is performed using the partner or donor’s white blood cells. This test is called the Leukocyte Antibody Detection test or “LAD” test. When antibodies to these blood cells are too low, your physician will consider means to boost them. For more information, click: Leukocyte Antibody Detection (LAD) test. 3 Natural Killer cell assay In addition to antibody tests, there are two tests that determine the relative activity of your immune system. The first of these is a test for natural killer cells. These are cells that circulate in your blood stream as well as entering the organs and tissues of the body. They survey the body for foreign materials such as bacteria and for the presence of abnormal cells. Natural killer cells can be quantified as a percent of circulating white cells. We have found that quantifying them provides excellent information regarding your ability to carry a pregnancy. High numbers of these cells has been associated with diminished capacity to carry a pregnancy. In addition to measuring natural killer cell numbers, an additional test will be performed that quantifies the killing activity of these cells. The killing activity will be monitored by repeated testing. If this killing activity is found to be elevated, your physician may determine that you need to be treated. For more information, click: Natural Killer Cell Assay. Th1:Th2 Cytokine Assay Another of immune cell function that is also performed is the Th1:Th2 Cytokine Assay. This test determines the relative balance of important cells in your immune system. Blood cells can be divided into different groups. It has been shown that prospective mothers with an increased ratio in one of these cell types carry a higher risk of unsuccessful pregnancy. This test aids the physician in determining whether or not pre-pregnancy treatment with drugs that reduce the numbers of cells that are excessive in number will be helpful. For more information, click: Th1:Th2 Cytokine Assay. T regulatory cell assay T regulatory cells are an important new marker in reproductive immunology. We have found our new T regulatory assay to be particularly useful in patients who have suffered chromosomally normal losses and also have normal NK and Th1:Th2 cytokine results. Most of these patients were found to have low levels of T regulatory cells. We have found that low numbers of T regulatory cells around the time of implantation identify women who are destined to lose their pregnancies. We have seen where rapid immunotherapeutic intervention appears to have salvaged these pregnancies. For more information, click: T regulatory cells. Endometrial biopsy The endometrial biopsy is a test that involves sampling a small piece of tissue removed from the lining of the uterus. Usually, the sampling is performed during the later part of the menstrual cycle eight to ten days following ovulation. Studies have found that increases in one type of natural killer cell were associated with immune dysfunction in the mother that hindered successful pregnancy. Subsequently, other investigators began to look at the number of T regulatory cells present in the tissue for further evidence of prospects for successful pregnancy. 4 When a tissue sample is submitted to the laboratory, special staining techniques are used for the detection of certain natural killer cells that carry a specific marker known as “CD57” and separately another marker that is found on T regulatory cells known as “FoxP3”. Together, these markers are used to assess the “receptiveness” of the lining of uterus for fetal tissues. For more information, click: Immune pathology of the endometrium. 5 Section II. Treatments A. Anticoagulants There are three injectable anticoagulants that we use. These medications are unfractionated heparin, Lovenox® (Clexane®) and Arixtra® and they are given by subcutaneous injections once or twice a day. These drugs do not cross the placenta so there is no fetal exposure. Numerous studies do not demonstrate an increase in birth defects. Oral anticoagulants should not be used in pregnancy as they can cross the placenta and can cause birth defects in babies. i. Heparin Unfractionated heparin (heparin sodium) is used infrequently for long term therapy in patients who have antiphospholipid antibodies or immunological infertility. It has been replaced by the fractionated low molecular weight heparins, Lovenox® or the synthetic product Arixtra®. These two drugs are safer and more convenient than heparin. ii. Lovenox®/Clexane® (enoxaparin sodium) Lovenox ®(or Clexane®) is a low molecular weight heparin that has less binding to blood proteins and thus has a more predictable dose response than unfractionated heparin. For this reason blood tests to monitor for the proper dose of the medication are not required. Instructions Pre-filled syringes with the appropriate dose of Lovenox ® makes the subcutaneous injections more convenient. The usual dose is 30-40 mg once or twice daily as directed by your physician. We recommend starting the once daily injection on cycle day 6 of your conception cycle. If you are doing an egg retrieval or other surgical procedure you need to stop the Lovenox® for 48 hours prior to the procedure and restart the injection 24 hours after the procedure. If you do not conceive, stop Lovenox until cycle day 6 of your next attempted cycle. With a positive pregnancy test, increase the dose of Lovenox to twice daily about 12 hours apart. Depending on your clinical condition, the injections will be stopped at the end of the first trimester (13-14 weeks), the end of the second trimester (26-27 weeks), or prior to labor or as recommended by your physician. 6 Side effects and risks of Lovenox®/Clexane® 1. Bruising- the most common side effects of the injectable anticoagulants is burning, bruising, and oozing of blood from the injection site. Occasionally a small lump (“hematoma”) may form. This can be controlled by pressure and ice. There is also rare staining of the skin from the bruising under the skin. 2. Bleeding- The most serious risk is bleeding. Fortunately, this is rare. You should notify your physician if you have frequent nose bleeds, vomiting blood, blood in urine or stool, vaginal bleeding, intense headaches or abdominal pain. You should not start the injections if you are actively bleeding. Spinal and epidural anesthetic pose an increased risk of a hematoma in and around the spine that may cause long term or permanent paralysis. 3. Thrombocytopenia-This is a condition of low platelet counts. This condition can increase the risk of bleeding. Heparin and the other anticoagulants can cause thrombocytopenia, however the prevalence is less with Lovenox or Arixtra than unfractionated heparin. iii. Arixtra® (Fondaparinaux sodium) Arixtra® is a synthetic anticoagulant that works by inhibiting Factor Xa. Other anticoagulants inhibit multiple factors in the coagulation process. Therefore Arixtra® is not a heparin and the risks of thrombocytopenia is less than with Lovenox® or heparin. It has a longer half life than Lovenox® and is given as a once a day injection. Studies done with our patients reveal equal successful results with Lovenox ®or Arixtra®. Instructions Prefilled syringes with appropriate dose of Arixtra® makes the subcutaneous injections more convenient. The usual dose is 2.5 mg once daily. Please see instructions section under Lovenox® since it is the same. Side effects and risks See section on side effects and risks of Lovenox®. Bruising and burning appear to be less with Arixtra cpompared to Lovenox®. The risks of bleeding appears to be identical to Lovenox®. Contraindications to Lovenox® or Arixtra® 1. Kidney disease 2. Active bleeding 3. Bleeding ulcers 7 4. 5. 6. 7. Infection of the heart Low platelet counts (idiopathic thrombocytopenia purpura or “ITP”) History of stroke Uncontrolled high blood pressure Instructions for administration of Lovenox®/Clexane® or Arixtra® The medicine should be injected in the subcutaneous tissue of the lower abdomen or in the hip and buttock’s area. The entire length of the needle should be introduced into a skin fold held between the thumb and forefinger. To minimize bruising, do not rub the injection site. Ice can also be used. See following instructions: 1. Remove the needle shield by pulling it straight off the syringe. If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient. 2. Inject using standard technique, pushing the plunger to the bottom of the syringe. 3. Remove the syringe from the injection site keeping your finger on the plunger rod. 8 4. Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation. 5. Immediately dispose of the syringe in the nearest sharps container NOTE: The safety system can only be activated once the syringe has been emptied. Activation of the safety system must be done only after removing the needle from the patient's skin. Do not replace the needle shield after injection. The safety system should not be sterilized. Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others. 9 B. Low dose aspirin Low dose aspirin (81-100mg) treatment is often utilized for women with recurrent pregnancy losses and infertility caused by immunology factors. It may be prescribed alone or in combination with heparin or other blood thinners in women with an inherited or acquired thrombophilia. Side effects and risks Side effects are rare but include nausea, upset stomach, heartburn, decreased appetite and microscopic amounts of blood in stools. Women who active peptic ulcers or have allergies to aspirin should not take low dose aspirin. Patients with asthma sensitivities to NSAIDS (Advil®, Celebrex®, Aleve®) or are on steroid medication should take low dose aspirin cautiously. Use in pregnancy The use of aspirin should be avoided in the last 3 months of pregnancy or while breast feeding unless recommended by your physician. 10 C. Metformin (Glucophage®, Riomet®) Metformin is a medication used in the treatment of Type II Diabetes (adult onset). It is also used for the treatment of insulin resistance seen in women with Polycystic Ovarian Disease (PCOD). To diagnose insulin resistance (IR) we use the HOMA test. This is a ratio of fasting insulin to fasting glucose divided by a constant that your doctor will calculate. The degree of IR is a HOMA score greater than 1. So a HOMA score of 3 has more resistance to insulin than a score of 2. We will often treat patients with Metformin if the values are between1.8 to 2.0. Dosage The usual dosage is 500mg twice daily. The maximum dose is 2500 mg/day in divided doses or 2000 mg/day if the extended release preparation is used (GlucophageXR®). The medicine should be taken with meals. Side effects of metformin The most common side effects are nausea, bloating, flatulence, diarrhea and abdominal cramps when first taking Metformin. We recommend starting with 1 pill a day for 4 days and then increasing to 1 pill in the morning and evening. There is a rare complication called lactic acidosis which is a build-up of lactic acid in the blood. The symptoms of lactic acidosis are nausea, weakness, sleepiness and increasing respiration. Alcohol can potentiate the effect on lactate metabolism. Alcohol should be avoided while taking Metformin as it can also increase chest pain and muscle aches (flu-like symptoms). Usage in pregnancy It is a category B drug (probably no risks) but once you conceive you should speak to your obstetrician for guidance. Many will continue the medication through the first trimester or longer. 11 D. Levothyroxin sodium (Levoxyl®, Levothyroid®, Synthroid®) Levothyroxin is a synthetic thyroid medication used to treat hypothyroidism. TSH and T4 blood tests are done to determine medication need. The higher your TSH level the more hypothyroid you are. The diagnosis of hypothyroidism is determined when the TSH value greater than 4.0 however many doctors will not treat at this level unless the patient has symptoms. The average TSH value for a woman who is not pregnant is 2.5. The value for the average pregnant woman is 1.5. In women who are infertile or having immunology issues we tend to treat in the 3.5-4.0 level with low dose Levothyroxin. During pregnancy the TSH value needs to be rechecked because the dose may need to be increased. Adult dosage There are many different dosages ranging from 25-200 micrograms. It is important to be on the proper dose. Too much thyroid replacement medication can increase the risk of osteoporosis and hyperthyroidism. The medication should be administered in the morning 30 minutes before food with a full glass of water. Check with your pharmacist if you are taking multiple medications to see if there are any drug interactions. 12 E. Dexamethasone/Prednisone Dexamethasone and prednisone are oral synthetic corticosteroids that suppress the immune system and inflammation. These drugs mimic the action of cortisol which is a natural occurring corticosteroid produced in the body by the adrenal glands. Corticosteroids may be prescribed if you test positive for ANA (antinuclear antibodies), antibodies to DNA or histones or other autoantibodies. In reproductive immunology, low dosages for short periods of time are used. This tends to minimize the side effects and risks of corticosteroid medication. Dosage Dexamethasone – 1 mg per day starting on cycle day 6 in the menstrual cycle you are attempting to conceive. If no pregnancy results, stop the medication with onset of menses until cycle day 6 of the next attempted cycle. If pregnant, continue the dexamethasone until you are 11 weeks and then taper off the medication. Prednisone- 10 mg per day starting cycle day 6 in the menstrual cycle you are attempting to conceive. If no pregnancy, stop the medication with the onset of menstrual flow until cycle day 6 of the next attempted cycle. If pregnant, increase the dose to 20mg (10mg in the morning and 10 mg in the evening). At 11 weeks, taper off the prednisone. Tapering off With prolonged therapy and with high doses, corticosteroids can suppress the adrenal glands so they will not produce cortisol. For this reason, you must taper off (lower gradually) the medication to allow the adrenal glands to recover. There is no need to taper off the steroids if you are on them less than a month. The schedule for tapering off are as follows: Dexamethasone- At 11 weeks, take one half of a tablet (0.5mg) for 1 week, then one half of a tablet every other day for a week then stop. Prednisone- At 11 weeks, decrease from 20 mg to 10 mg for 1 week then use 5 mg/day for one week then 5 mg every other day for 1 week and then stop. Side effects/Risks 1. Stomach upset, nausea, reflux and ulcerations of stomach, esophagus and duodenum can occur with corticosteroid use. 13 2. Since corticosteroids have an immunosuppressant action on the body, bacterial, viral and fungal disease may progress more easily. 3. Increased appetite and water retention can lead to weight gain. A puffy face (round face) may occur along with skin stretch marks (stria) and abdominal obesity. 4. Loss of calcium from the bone (osteoporosis) may increase the risk of bone fractures. 5. High blood sugar, muscle weakness, mood changes, nervousness, headaches, glaucoma, cataracts and high blood pressure have all been reported. As mentioned previously, the side effects and risks are increased with high doses and for prolonged periods of use. Most side effects, if they occur, will disappear with cessation of the medication. Helpful hints while taking corticosteroids: 1. Take your medications with food. This may help with stomach and esophageal irritation. 2. There may be a need to reduce calories and increase exercise to prevent weight gain. 3. Exercise is also important to prevent weakness and bone thinning. 4. Take adequate doses of calcium (1500 mg/day) and vitamin D (1000 IU /day). This can help prevent bone thinning and osteoporosis. 5. Avoid being around people who are sick and have infections. Do not receive live virus vaccinations while on corticosteroids. 6. Avoid drinking alcohol and limit use of aspirin, Advil (ibuprofen) and Aleve. These may all increase the risk of gastric ulcerations. Dexamethasone/prednisone use in pregnancy There are no well controlled studies on fetuses exposed to corticosteroids. The Collaborative Perinatal Project followed a number of women during the first trimester. The data showed no increase in birth defects. Studies in rodents with high doses of steroids showed an increased incidence of cleft lip. 14 F. TNF-alpha inhibitors (Humira®/ Enbrel®/Simponi®) TNF-alpha inhibitors are prescribed when laboratory work shows an increased tumor necrosis factor alpha/ interleukin-10 (TNF alpha/IL-10) ratio in the blood or increased CD57+ cells in the uterus. Increased TNF-alpha/Il-10 ratios and CD57 uterine cells have been associated with recurrent miscarriage and repeated IVF failures. TNF-alpha inhibitors are drugs that lower TNF alpha/IL-10 ratios. It is approved by the FDA for treatment of rheumatoid arthritis, Crohn’s disease, moderate to severe plaque psoriasis, ankylosing spondylitis and a few other forms of arthritis. It has not been studied by the FDA for patients with recurrent miscarriage or IVF failure. Humira® is given as a subcutaneous injection under the skin of the stomach or thigh every other week. Simponi® is given as a subcutaneous injection once a month. When treating arthritis, the injections may continue for years or indefinitely. For reproductive problems the injections are given for one to three months and then stopped. Risks and Side effects of TNF-alpha inhibitors Minor side effects: 1) Skin irritation at the injection site may occur in 20% of patients. In studies, patients receiving a placebo injection (no medication) had a 14% incidence of injection site reactions. 2) Skin rash occurs in about 3 of 1000 patients. 3) Minor infections, such as bronchitis, bladder infection or a upper respiratory infection, i.e. colds, occurred in 1 per patient year. In the placebo group it was 0.9 per patient year (A “patient year” is the prevalence of infection for a patient taking the medication for one year). 4) Headache, sinus pain, stomach pain, or nausea may occur. Severe side effects: 1) Serious infection occurs in 4 per 1000 per year as compared to the placebo group of 2 per 1000 per year. These infections include pneumonia, diverticulitis and kidney infection. 15 2) Tuberculosis can be reactivated when using Humira®. The incidence of reactivation in women 1iving in the U.S. and Canada was 0.07 per 100 patient years. This means 7 in 10,000 patients taking Humira® for 1 year had a reactivation of tuberculosis. For this reason women who take this medication should have a negative tuberculin skin test. If a patient has a positive test, a blood test called Quantiferon Gold needs to be done. If no prior treatment was given for tuberculosis, the patient would need to start on tuberculosis treatment before starting the TNF-alpha inhibitors or avoid taking the TNF-alpha inhibitors 3) Hepatitis B virus reactivation can occur when using TNF-alpha inhibitors. If you are a carrier of Hepatitis B, (positive Hepatitis B surface antigen, HBsAg), TNF-alpha inhibitors may cause a reactivation of the virus. Patients who are positive for HBsAg need to have liver function tests monitored during therapy or avoid taking the TNF-alpha inhibitors 4) Other very rare side effects include A) a possible increased incidence of lymphoma in patients on long term therapy. B) decreased white blood, cells, red blood coils and platelets (pancytopenia) have boon reported, C) patients who have a neurological disease such as multiple sclerosis, myasthenia gravis or Guillain-Barre Syndrome should not take the TNF-alpha inhibitors D) a Lupus-like syndrome may occur with a positive anti-nuclear antibody test. Use of TNF-alpha inhibitors in pregnancy Studies of the TNF-alpha inhibitors in pregnant monkeys in large doses have revealed no birth defects or developmental abnormalities in the offspring. They are listed by the FDA as pregnancy category B drugs. However, there are no well controlled studies in women. It is not recommended that patients conceive while on TNF-alpha inhibitors until further studies are done. Alternatives to Humira®/Simponi® in women with increased TNFalpha/IL-10 For patients who are allergic to Humira® or Simponi®, there are other TNF alpha inhibitors that can be used such as Enbrel®. Enbrel® has similar risks and side effects of Humira® and Simponi®. Other treatments that have been used for increased serum TNF alpha/IL-10 or increased CD57+ cells in the uterus is administration of IVIG (intravenous gammaglobulin). What should you avoid while taking the TNF alpha inhibitors Avoid contact with people who have colds, the flu or other contagious diseases. Avoid taking live vaccines. You should check with your doctor before receiving any vaccinations. You should report any fever, weight loss, chronic cough, difficulties with breathing, fatigue, easy bruising, joint pains, numbness and tingling in the legs or nausea and vomiting to your doctor. 16 G. Intravenous Immunoglobulin G (IVIG) Intravenous immunoglobulin therapy (IVIG) is a concentration of antibodies that is obtained from human donors’ blood. The blood has been screened for infectious diseases according to the Food& Drug Administration (FDA) guidelines. The manufactured solution is free of any blood cells and is highly purified. It is treated by two different processes that sterilize the blood so it is free of any bacteria or viruses. IVIG therapy has been recommended and is clinically beneficial in some patients with immune disorders. These disorders include increased natural killer cells in the blood and uterus, increased natural killer cell activity (cytotoxicity), increased production of TH1 cytokines and decreased levels of T regulatory (Treg) cells. Procedure An IV is started in the hand or arm and the solution is infused slowly over 2 ½ 3 hours. Additional doses may be required depending on the response to the follow-up blood work in several weeks. Occasionally a dose is given prior to embryo transfer in an IVF cycle. If pregnancy hormones cause a spike in natural killer cell activity, an infusion of IVIG may be required in early pregnancy. Side Effects and Risks Side effects and risks of IVIG are uncommon. 1. Approximately 5% of patients may have headaches, backaches, muscle aches, fever, chills, flushing, nausea or vomiting. Some patients may experience a delayed reaction, having headaches or nausea 24-74 hours after an infusion. 2. As with all infusions, bruising, swelling, rash and infections may occur at the infusion site. 3. Transmission of viruses. There have been no reported cases of AIDS or Hepatitis virus transmission when using solutions are prepared with the virus inactivation process. 4. Patients with an IgA deficiency may have a reaction to IVIG and even anaphylactic shock. We require all patients to have a blood test for IgA, IgM, IgG antibodies prior to an infusion. This reaction is very rare. 5. An inflammation of the membranes around the brain and spinal cord called aseptic meningitis has been reported. It is estimated to occur in 12 per 10,000 patients infused. It is not dangerous but can be debilitating for a short period of time. 17 6. There may be others risks of IVIG that are unknown. There are no reports of problems with future blood transfusions or organ transplants in patients receiving IVIG. Costs of IVIG Unfortunately IVIG is expensive. In some cases, insurance companies may reimburse the patient for IVIG. How to arrange for IVIG infusions Please contact our office so that we can help you arrange for infusions. 18 H. Intralipids Intralipids are a fat emulsion solution used as a nutritional supplement in patients with nutritional deficiencies. It is a synthetic product that has 10% soybean oil, egg yolk phospholipids, glycerin and water. It also contains a small amount of aluminum (25mcg/L). It is administered intravenously (injected in the vein). Some recent studies have shown it may decrease the killing activity (cytotoxicity) of natural killer cells (NK cells). NK cells are part of the immune system that helps control infection and cancer growth. In infertility patients this may improve implantation and successful pregnancy outcome rates. The conventional treatment for increased cytotoxicity is an infusion of intravenous gamma globulin (IVIG). Procedure An IV is started in the hand or forearm and an infusion is given over 1-2 hrs. Side effects Side effects (SE) are rare but include an irritation or infection in the vein at the site of infusion. Other SE’s that occur in less than 1% of patients are: fever, chills, sweating, nausea, vomiting, dizziness, headaches, back pain, chest pain, shortness of breath and increased blood clotting. A deposition of pigment in lymph nodes, spleen and liver called “intravenous fat pigment” has been detected in experimental animals and patients after multiple intralipid infusions. The cause and significance of this finding is unknown. The safety of intralipids in pregnancy has not been established therefore it is not recommended for use in pregnancy. The FDA has rated intralipids as a category C drug although animal studies have not yet been done. Contraindications Intralipids should not be given to patients who have severe liver disease, recent heart attack or stroke or have any disease of fat metabolism. Patients with renal disease should not use intralipids because of possible aluminum toxicity. Women with allergies or sensitivities to soy products, egg yolks or egg whites may have a reaction to intralipids and should not use the medication. Advantages The advantages of intralipids versus IVIG are its lower cost and that it is not a blood product. Disadvantages 19 The disadvantages of intralipid therapy is that there are limited patient studies available on the efficacy and safety of the product in infertility patients. It also has not been studied in patients with other immune conditions such as low Treg cells or elevated Th1:Th2 cytokines. It has not been studied in combination with other medicines such as Humira® or Lovenox®. How to obtain Intralipids Please contact our office to arrange for an infusion. 20