Weapons Doctors Use to Fight Lupus Dr Weapons Doctors Use to Fight Lupus Dr. Barbara Mendez Assistant Professor at Albert Einstein Director of the lupus Clinic

Systemic Lupus Erythematosus (SLE) Introduction: Lupus is a complex autoimmune disease With excessive immune system activation Loss of tolerance of immune system to one’s body The immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage It can affect any part of the body or organ It is usually a chronic disorder with periods of remission and exacerbations

Etiology Currently unknown but environmental and genetic factors are involved Environmental factors: Ultraviolet light ( UVB), infections and current drugs ( ex. Hydralazine), hormones B cell activation results in increase auto-antibody production ( ANA , dsDNA) Failure to remove immune complexes from circulation lead to immune complex deposition in tissue which elicits inflammation There also seems to be impaired T cell regulation

Signs and symptoms differ from patient to patient

No major organ involvement Major organ involvement Lupus Management The goal to lupus management is to suppress inflammation in order to prevent organ damage caused by the inflammation Therapy intensity is determine by the severity and by the extend of organ involvement No major organ involvement Low dose steroids Antimalarials Methotrexate/Azathiopurine Assess severity and organ involvement Major organ involvement Cyclophosphamide Mycophenolate mofitil Calcineurin inhibitors Biologics Clinical trials

Corticosteroids Used for anti-inflammatory and immunosuppressant effect It is the fastest anti-inflammatory available Dosage depends on the severity of the disease Dosage should be decreased to the lowest level needed to keep disease under control

Corticosteroids Side effects: Increase appetite and weight gain Cushingoid face, buffalo bump Acne Mood swings and even psychosis Osteoporosis Glaucoma, cataracts Insomnia Diabetes High blood pressure Avascular necrosis Increase risk of infection Gastritis and peptic ulcers Muscle weakness delay wound healing Steroid withdrawal syndrome consists of lethargy, fever, myalgia following abrupt discontinuation Acute adrenal insufficiency may occur if drug is withdrawn abruptly ( can even cause death)

Antimalarials 3 types: Hydroxychloroquine (Plaquenil), Cloroquine, Quinocrine Mechanism: modulates the immune system without immunosuppressing or predisposing to infection Used for arthritis, skin manifestations and fatigue Hydroxychloroquine is the most commonly used Benefit: Prevent lupus from spreading to certain organs ( kidney and CNS) Reduce flares by 50% Reduce mortality Antithrombotic effects Lower cholesterol Reduces neonatal lupus ( fetal heart block)

Hydroxychloroquine Side effects: are usually rare and minor Stomach upset/bloating Eye toxicity-retinopathy ( more with Chloroquine). Occur in about 1 out 5000 patient who take this for more than 5 years Headache Myopathy Skin hyperpigmentation Rare cardiomyopathy Safe in pregnancy Smoking interferes with Hydroxychloroquine activity

Methotrexate Good for skin manifestations, arthritis and modest lupus activity It is a chemotherapy agent but in rheumatology is not used at in chemotherapy doses Old drug used for many different types of inflammatory arthropathies Usually taken with folic acid which can protect from many of the side effects of methotrexate Patient with Kidney disease may need dose reduction or adjustment

Methotrexate Side effects : Bone marrow suppression: reduce blood counts ( reduce WBC, platelets or anemia) Liver toxicity Hair loss and oral ulcers Pneumonitis ( cough and shortness of breath) Increase risk of malignancy ( Lymphoma, skin Cancer and lung cancer in patients with RA and IBD ) Diarrhea, nausea,vomiting , anorexia Defective spermatogenesis infertility Increase risk of infection Teratogenic: can cause fetal death and congenital abnormalities and is found in breast milk.

Management of lupus: major organ involvement We use stronger immunosuppressive treatments The evidence for the effectiveness of these therapies in lupus are derived from studies of lupus nephritis Cyclophosphamide Mycophenolate mofitil Calcineurin inhibitors Biologics ( Rituximab or Benlysta ) Clinical trials

Example: lupus nephritis management Treatment is determined by the kidney biopsy findings Class I or II : no immunosuppression needed Class III or IV: treat aggressively Cyclophosphamide ( Eurolupus vs NIH protocol) + steroids Cellcept + steroids Class V : cellcept + steroids Maintance: Azathiopurine or Cellcept For patients with lupus nephritis who do not respond to Mycophenolate or Cyclophosphamide: we add rituximab or Calcineurin inhibitors

Cyclophosphamide ( Cytoxan) Use to be the drug of choice for lupus nephritis and for any major organ involvement This is chemotherapy and it is used in 2 different doses NIH protocol ( 0.5-1g/m square) monthly x6 followed by every 3 months Euro lupus ( low dose 500mg every 2 weeks x6). However does not work as well in Blacks and Hispanics Side Effects: Bone marrow suppression: Reduce blood counts usually noted day 8-12 after infusion Increase risk of infection Hair loss or alopecia Sterility is age dependent ( looking at the NIH cyclophosphamide protocol- sterility occurred in 12% of those < 25 years old, 27% of those < 30 years, and in 62% of those ≥ 31 years).  Lupron use may help preserve ovarian function Increase of risk of malignancy is dose dependent (bladder cancer, lymphoma, leukemia and skin cancer) Bladder Bleeding ( AKA: Hemorrhagic cystitis) usually we give Mesna and fluids to reduce this risk In kidney disease you need to reduce dose

Mycophenolate mofetil (Cellcept) It is an immunosuppressive agent that reduces lymphocyte activity Clinical trials have shown that Mycophenolate is as effective as Cyclophosphamide for induction of remission and is associated with fewer adverse events Mycophenolate is now frequently preferred over Cyclophosphamide in lupus nephritis and other major organ manifestations Mycophenolate also seems to work better when compared to Cyclophosphamide for patients that are Black and Hispanic

Mycophenolate Mofitil (Cellcept) cont. GI: nausea, diarrhea, abdominal cramping in 20-50%. These symptoms are tolerated better with time and rarely requires cessation of the drug Bone marrow suppression: low Blood counts Hypertension and peripheral edema Predispose to infection including opportunistic infections, reactivations of Hep B or hep C and JC virus Potential increase risk of lymphoma Antacids, mineral supplementation ( Magnesium, calcium) Sevelamer, PPI ( omeprazole) can reduce gut absorption of the drug and reduce the levels in the blood Teratogenic: can cause fetal abnormalities. It is recommended that 2 forms of contraception is used.

Azathiopurine ( Imuran) Used in maintenance or after induction of a remission of a major organ manifestation Bone marrow suppression: Reduce blood Nausea/vomiting Diarrhea Acute Pancreatitis Increase risk of Infection Increase risk of Lymphoma Safe in pregnancy

Calcineurin inhibitors 2 types Tacrolimus Cyclosporin Used as Adjunct therapy to Mycophenolate when there is a major organ involvement that is not responding as desired It is also a potential alternative for induction/maintenance therapy in lupus nephritis In lupus nephritis it is helpful in reducing the amount of protein loss in urine Cyclosporin is safer than Mycophenolate in pregnancy Topical Tacrolimus used for lupus skin manifestations

Calcineurin Inhibitors Side Effects: high blood pressure Hyperglycemia and diabetes Increase cholesterol Electrolyte abnormalities with low magnesium and high potassium Gi: vomiting , diarrhea Liver toxic , pancreatitis, peptic ulcers, Mood changes, insomnia, loss of appetite increased risk of infection increased risk of lymphoma and skin cancer itchiness Tremor Unwanted enlarged gums or hair growth Neuropathy: Numbness ,tingling or burning sensation Convulsion/seizures Hyperurecemia which can lead to gout ] Kidney dysfunction Many drugs can cause a drug-drug interaction such as antibiotics and even grapefruit . Avoid grapefruit Mechanism: inhibits transcription factors that upregulate cytokine production

Rituximab Reduces B cells and reduces auto-antibody production which is seen in lupus It is used in patients who have failed conventional therapy Infusion reactions: usually resolves by slowing down the infusion rate however there have been Fatalities associated with infusion reaction. Mucocutaneous reactions Hepatitis B reactivation with fulminant hepatitis ( always check hepatitis status prior to administration) Increased Risk of infection including Progressive multifocal leukoencephalopathy which is a brain infection that can lead to death Prolong Cytopenias ( Low blood counts) and hypogammaglobulemia ( Low antibody production) Cardiac arrhythmias

Benlysta First drug in over 50 years approved by FDA for lupus patient with positive dsDNA and low complements It inhibits B lymphocyte stimulator (BLyS) or B cell growth factor and thus prevents further activation and proliferation of B cells Improves musculoskeletal and skin manifestations Improves immunologic parameters ( dsDNA and complement) Improves blood counts (platelets, anemia) Trials excluded patients with severe lupus nephritis or severe CNS manifestations

Benlysta Side Effects: Nausea/diarrhea Depression/insomnia Infusion reaction Increase risk of infection Muscle ache

Summary Today lupus is a treatable chronic disease with relatively good prognosis Steroid are always first line given that they work quickly and they are excellent anti-inflammatory Immunosuppression is standard of care and used to reduce inflammation and prevent irreversible organ damage The amount of immunosuppression needed is determined by the severity of the organ involvement Most medications that suppress the immune system have multiple toxicities however most of the time these medications are well tolerated with little serious side effects Always talks to your doctor about risk and benefits of any medication to see what will work best for you