1. 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

2. 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

3. 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

4. Signs and symptoms differ from patient to patient

5. 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

6. 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

7. 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Acute adrenal insufficiency may occur if drug is withdrawn abruptly ( can even cause death)

8. 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)

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

10. 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

11. 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.

12. 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

13. 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

14. 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

15. 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

16. 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.

17. 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

18. 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

19. 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

20. 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

21. 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

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

23. 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