Immunosuppressive Therapy in Systemic Lupus Erythematosus

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Immunosuppressive Therapy in Systemic Lupus
Erythematosus

• Jim Oates, MD
• Associate Professor of Medicine
• Department of Medicine
• Division of Rheumatology

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Outline

• Lupus
• Definition
• Levels of disease severity
• Therapies
• Individual medications
• Mechanism
• Dosing
• Toxicity
• Monitoring

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Lupus

• Systemic autoimmune disease manifested by
• Autoantibody production
• End organ inflammatory disease from
  autoantibodies
• Taylor therapy to the most severe organ
  involvement
• Therapy is long term (years)

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Malar rash Oxford Textbook of Rheumatology 3rd
edition
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Mild disease

• Mild photosensitive lesions
• SPF 30 or greater
• Avoid sun/cover skin with SPF clothing
• Hydroxychloroquine
• Arthralgias, mild arthritis
• Hydroxychloroquine
• Non-steroidal anti-inflammatory drugs (NSAIDs)

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Discoid lesions Oxford Textbook of
Rheumatology 3rd edition
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Refractory Skin Disease

• Discoid lesions, bullous lesions, severe
  maculopapular lesions
• Topical or intralesional corticosteroids
• Topical tacrolimus
• Mycophenolate mofetil
• Azathioprine
• Dapsone

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Serositis

• Pleuritis, Pericarditis, Arthritis
• Treatment advanced with symptoms
• NSAIDs
• Corticosteroids
• Steroid sparing agents
• Methotrexate
• mycophenolate mofetil
• azathioprine

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Ed Friedlander, M.D., http//www.pathguy.com/lectu
res/bad_lupus.jpg
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Severe Disease

• Vasculitis, nephritis, CNS vasculitis or
  vasculopathy, hemorrhagic alveolitis
• Pulse 15 mg/kg/day methylprednisolone
• Induction agents
• Cyclophosphamide
• Mycophenolate mofetil
• Plasmapheresis for life threatening acute disease
  (hemorrhagic alveolitis)

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Severe disease

• Maintenance therapies (once remission induced)
• Mycophenolate mofetil
• Azathioprine

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Refractory Disease

• Rituximab
• IV human immune globulin

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Hydroxychloroquine (Plaquenil)

• ?-hydroxylated chloroquine
• Less ocular toxicity than chloroquine
• Originally used to treat malaria, later found
  effective in rheumatoid arthritis and lupus
• Concentrates in lysosomes and has
  anti-inflammatory properties

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Hydroxychloroquine (Plaquenil)pharmacology

• GI absorption 74
• High uptake in melanin-containing tissues
• Epidermis
• Retina
• Metabolized by the liver
• Excretion via the kidney
• t½ 50 days (measurable in urine after 2-4 months)

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Hydroxychloroquine (Plaquenil)dosing

• 200 mg daily x 1 week
• Increase to 200 mg twice daily after 1 week
• Reduces GI disturbances (diarrhea, nausea), which
  are self limited (2 weeks)
• Does not appear to reduce headache (rare)

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Hydroxychloroquine (Plaquenil)toxicity

• Retinal
• Baseline ocular examination and CMP
• If normal, no screening
• Annual screening if dose 6.5 mg/kg/day or
  baseline exam abnormal or liver/renal impairment
• Color vision, peripheral vision (Amsler grid),
  retinal exam
• GI

Levy GD, et al. Arthritis Rheum.
1997401482-6. Buckley R. Eye 1998 12907
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Azathioprine (Imuran, Azasan)

• Inhibits purine metabolism via metabolite
  6-mercaptopurine (6-MP)
• Metabolized to 6-MP by red cell glutathione
• 6-MP metabolized by xanthine oxidase and
  thiopurine methyltransferase (TPMT)
• Co-administration with allopurinol
  contraindicated
• Screen for TPMT deficiency (0.3 of population)
• t½ 3 hours

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Azathioprine (Imuran, Azasan)dosing and
monitoring

• Typical final dose 2 mg/kg/day given PO in AM
• Starting dose 50 mg PO daily
• Advance dose (25 mg) q 7-14d after CBC confirmed
  normal
• Once at final dose, CBC every 4-6 weeks

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Azathioprine (Imuran, Azasan)Toxicity

• GI toxicity limiting in some
• Rare hepatitis or pancreatitis
• Rare hypersensitivity reaction in first weeks
• fever, rash, myalgias, liver function test
  abnormalities, gastrointestinal symptoms, and
  hypotension
• Immune suppression live vaccine
  contraindicated, influenza/pneumococcal vaccine
  encouraged
• Lymphoma

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Mycophenolate Mofetil (CellCept)

• Inhibits inosine monophosphate (IMP)
  dehydrogenase and thus purine synthesis
• Results in reduced B and T lymphocyte
  proliferation and antibody production
• Hydrolyzed to mycophenolic acid in GI tract
• t½ 12 hours
• Liver metabolism, clearance of inactive
  metabolite in urine and feces

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Mycophenolate Mofetil (CellCept)Dosing

• 1.5-3g daily given BID to TID
• Up to 25 better absorption if given on empty
  stomach
• Antacids reduce absorption
• Initiate with 500 mg PO daily or twice daily
• Evaluate for marrow toxicity (CBC)
• May promote GI tolerance
• TID QID dosing better tolerated

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Mycophenolate Mofetil (CellCept)Monitoring and
Dose Increase

• After initial dose, CBC every 1-2 weeks as
  increase dose by 500 mg each time to final dose
• Monitor CBC every 4-6 weeks thereafter

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Mycophenolate Mofetil (CellCept)Toxicity

• Immunosuppression live vaccine contraindicated
  while influenza and pneumococcal vaccine
  indicated
• Marrow toxicity
• GI toxicity
• May be teratogenic
• Reduces blood levels of oral contraceptives
• ? Increased lymphoma risk

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Mycophenolate Mofetil (CellCept)Tricks for dosing

• GI side effects less if taken with food
• Mycophenolic acid (Myfortic) better tolerated
  (360 mg dose equivalent to 500 mg of
  mycophenolate mofetil)

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Cyclophosphamide (Cytoxan)

• Alkylating agent
• Depletes B and T cells
• Liver metabolism to
• 4-hydroxycyclophosphamide
• Aldophosphoramide
• phosphoramide mustard (active ingredient)
• acrolein (bladder toxicity)
• Renal excretion within 48 hours

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
28
Cyclophosphamide (Cytoxan)Toxicity

• Infiltration causes extensive tissue necrosis
• Hemorrhagic cystitis and bladder cancer
• Immunosuppression opportunistic infection
• Live vaccine contraindicated
• Pneumococcal and influenza vaccine indicated
• Hematopoietic malignancy (rare)
• Infertility (common)

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
29
Cyclophosphamide (Cytoxan)Toxicity

• Hepatitis with cholestasis (rare)
• Pneumonitis (rare)
• Hypersensitivity (rare)
• GI toxicity (nausea, vomiting, diarrhea common)
• Alopecia (common)
• Teratogenic

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Cyclophosphamide (Cytoxan)Infertility planning

• Gonadotropin-releasing hormone agonist Lupron
  Depot 3.75 mg IM 10 days before each dose for
  women
• Sperm banking for men

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Cyclophosphamide (Cytoxan)Dosing for pulse IV
therapy

• Initiated at 750 mg/m2, dose reduced for reduced
  renal clearance (mg/m2)
• Nadir WBC 7-14 days after dose
• If nadir WBC
• If nadir WBC 4.0 k, increase dose (max 1000
  mg/m2)
• PCP prophylaxis (trimethoprim-sulfamethoxazole
  daily) more indicated for oral daily dosing

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
32
Cyclophosphamide (Cytoxan)Protocol for pulse IV
therapy

• Start IV, ensure good venous return
• Mix in 150 mL normal saline or D5W given over 60
  min.
• MESNA 20 of the CYC immediately before CYC and
  every 3 hours for a total of 4 doses.
• Dexamethasone 10 mg orally 34 hours after CYC.
• Ondansetron 16 mg IV premed then 8 mg PO q 12
  hours x 2-3 days.

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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CyclophosphamidePrevention of bladder toxicity

• Hydration with D5 ½ NS at 150200 mL/h for a
  total of 24 L.
• Drink fluid (2 liters) for the rest of the day
• Bladder irrigation may be used if patient unable
  to tolerate intravenous fluids.

Seo P. Therapies. In Current Rheumatology.
Imboden J. ed. McGraw Hill 2004.
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Cyclophosphamide (Cytoxan)Daily Oral Therapy

• Initial dose 50 mg daily in the AM with 1 liter
  of fluid (throughout the AM)
• Increase every 7-14 days after CBC check
• Final dose 1-2 mg/kg/day
• CBC every 4-6 weeks thereafter
• trimethoprim-sulfamethoxazole daily

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Human Immunoglobulin

• Pooled human immune globulin (95 IgG)
• Modulates Fc receptor function, suppresses
  antibody synthesis, inhibits complement
  activation
• t½ 3 weeks after equilibration over 72 hours
• Contraindicated in IgA deficiency

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Human Immunoglobulincomplications

• Anaphylaxis (greater if IgA deficient)
• Fever, chills, back pain, shortness of breath
  (48-72 hours after infusion)
• Aseptic meningitis (48-72 hours)
• Increased viscosity and thromboembolism (rare)

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Human ImmunoglobulinAdministration

• 2g/kg total dose either 1g/kg/day x 2d or
  0.4g/kg/day x 5d
• Reconstitute in D5W or NS (gently swirl, avoid
  foaming) over up to 20 minutes
• Premedicate with acetaminophen and
  diphenhydramine
• GI upset with increased infusion rate

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Take home points

• Taylor therapy to most severe end organ disease
  (the disease must be worse than the drug)
• Monitor for toxicity
• Immunize and monitor for infection
• Initiate steroid sparing agents quickly
• Therapy is long term (years)