Immunosuppression

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IMMUNOMODULATING THERAPIES FOR NEUROMUSCULAR DISORDERS

Overview
Medications
Treatment strategies

Azathioprine
Corticosteroids
Cyclophosphamide
Cyclosporine A
Intravenous immunoglobulin
Methotrexate
Mycophenolate mofetil
Plasma exchange
Rituxan

OVERVIEW

NOTE: Most treatment strategies listed here are based on anecdotal evidence and personal experience.
GENERAL PRINCIPLES
- Choosing and using a medication: Consider Benefit:Risk ratio
- Drug dosing
- Use objective measures of drug efficacy
  - Quantitative strength testing
  - Functional testing
SPECIFIC MEDICATIONS
- Corticosteroids (Prednisone or Solumedrol) are used for long-term immunosuppression and relatively rapid onset of benefit (Months). Side effects are common.
- Cyclosporine A is an alternative to Prednisone for long-term immunosuppression and relatively rapid onset of benefit (Months). In doses used for neuromuscular disorders side effects are not common.
- Azathioprine provides long-term immunosuppression with relatively few side effects. It may be useful to reduce needed doses of corticosteroids. However, there may be a long latency before benefit begins, and some patients do not improve at all.
- Methotrexate can have a relatively rapid onset of benefit (Months). It can be useful when corticosteroids or Cyclosporine A are ineffective or contraindicated. With routine monitoring, serious side effects are uncommon.
- Cyclophosphamide is useful in immune disorders with life threatening features and in B-cell mediated disorders that respond to few other treatments. As it has serious side effects, cyclophosphamide should be considered a treatment of last resort.
- Plasma exchange (PE) and human immune globulin (IVIg) are used for rapid onset, short-term benefit when patients have life-threatening signs such as respiratory insufficiency, dysphagia, or severe weakness. They are the only treatments shown to be of benefit in Guillain-Barré syndrome. PE & IVIg are expensive but are occasionally used for chronic therapy when other treatments have failed.
- Rituximab may be useful in neuropathies with associated serum IgM autoantibodies. Over the short term Rituxan appears to have few side effects.
- Mycophenolate mofetil may be used for long term immunosuppression as primary agent or to spare toxicity due to other medications.

CHRONIC IMMUNE-MEDIATED NEUROMUSCULAR DISORDERS
General Treatment Strategies: Based on diagnostic test results

Features of Diagnostic Testing			Disease Examples	Treatments Commonly effective
Nerve conduction	Conduction Block		MMN CIDP	IVIg
EMG	Thoracic paraspinous denervation		Motor neuropathy	None
Antibodies	IgM monoclonal	Target antigen: Carbohydrate Antibody location: Serum	MMN MAG neuropathy Sulfatide neuropathy GALOP syndrome	Cyclophosphamide ? Rituxan NOT corticosteroids
	IgG polyclonal	Target antigen: Membrane protein Antibody location: Serum	Myasthenia gravis Lambert-Eaton Neuromyotonia ? CIDP	Corticosteroids Immunomodulation T-cell immunosuppression Plasma Exchange ? Intravenous immunoglobulin
		Target antigen: Intracellular protein Antibody location: Serum + CSF	Anti-Hu ganglionopathy	None
		Target antigen: Carbohydrate Antibody location: Serum	Acute motor neuropathy Miller-Fisher	IVIg
	IgG monoclonal	Target antigen: Unknown Antibody location: Serum	POEMS	Uncertain

SPECIFIC MEDICATIONS

Corticosteroids

Prednisone

Indications
- Significant disability due to disease symptoms
- Effective long term immunosuppression
- Relatively rapid effect desired
- Disease features mediated by inflammation or T-cells
- Specific neuromuscular disorders
  - Muscle
    - Inflammatory myopathies: Some
    - Muscular dystrophy: Duchenne; ? LGMD 2D
  - Neuromuscular junction
    - Myasthenia gravis
    - Lambert-Eaton myasthenic syndrome
  - Nerve
    - Chronic immune demyelinating polyneuropathy (CIDP)
    - Vasculitis & Vasculopathies

Usual doses: Start at high dose then taper

Solumedrol: 1 gram iv daily for 3 to 5 days
Prednisone: Usually start at
50 mg to 100 mg per day (1 mg/kg/day): Single daily dose in the morning
- Exception: Myasthenia gravis
  - Start at lower dose: 10 mg qd
  - Then gradually increase up to 50 mg qd
  - With respiratory or bulbar symptoms: Pretreat with plasma exchange

Maintenance

Glucocorticoid
Side Effects

Cushingoid features
Weight gain
Bone
Avascular necrosis
Osteoporosis
Myopathy
Myosin-loss
Type II atrophy
Diabetes
Skin: Acne; Striae
Hypertension
Psychosis & Mood change
Pseudotumor cerebri
Glaucoma
Infection

Solumedrol (Methylprednisolone)
- Start at 1 gm/week iv for 1 month
- Then 1 gm every 2 weeks for 2 months
- Taper further by increasing time between doses
Prednisone
- Start taper after: 3 to 6 months; or clinical improvement begins
- Taper slowly by 5 mg every 2 to 6 weeks
Risk of recurrent symptoms with taper: Varies with disease type
- Myasthenia gravis: > 90% recurrence if steroids stopped without other Rx
- Inflammatory myopathy: ~ 50% recurrence risk
- CIDP: Relapse more common
  - Disease course > 1 year
  - Adults > Children

Monitor: Weight; Blood pressure; Blood glucose & electrolytes; Ocular exam
Advantages of corticosteroid therapy
- Short onset of action (1 to 3 months)
- Effective in majority of patients with specific disease indications
- Can be used in pregnancy
- Inexpensive
Disadvantages of corticosteroid therapy
- Transient initial severe exacerbation, usually after 1 to 3 weeks (2% to 5%)
- Many long-term side effects: Fewer with intermittent solumedrol
Drug combinations: Corticosteroids +
- Azathioprine: Steroid sparing
- Cyclophosphamide: Additional efficacy, but High toxicity
- Medications to prevent osteoporosis

Azathioprine (Imuran)

Azathioprine

Indications
- Long-term immunosuppression when rapid onset is not necessary
- Steroid sparing desired
- Minimize side effects
- Disease features mediated by inflammation or T-cells
- Specific neuromuscular disorders
  - Myasthenia gravis
  - Inflammatory myopathies: Some; For steroid sparing effect
  - ? Chronic immune demyelinating polyneuropathy (CIDP)
Usual doses
Initial: 2.5 to 3 mg/kg qd
- Maintenance: 1.5 to 2.5 mg/kg qd
Monitor
- Pretreatment: Thiopurine methotransferase (TMPT)
- Chronic: Hematocrit, WBC & platelets; Liver function
Advantages
- Few subjective side effects
Disadvantages
- Serious side effects
  - Flu-like reaction: 20% to 30% of patients; Azathioprine cannot be restarted
  - Hematologic
    - Reduced RBC, WBC, Platelets: Megaloblastic anemia; Cytopenia
    - Dose related or idiosyncratic
  - GI: Liver dysfunction; Pancreatitis
  - Teratogenicity
  - Increased risk of malignancy
    - Lymphoproliferative disease: Up to 60x risk in transplant patients
    - Other: Cervical atypia; Skin cancers, including aggressive squamous cell carcinomas
    - Not demonstrated in neuromuscular autoimmune disease patients
- Long onset of action (6 to 24 months)
- Moderate to high cost
Drug combinations: Azathioprine +
- Corticosteroids: For steroid sparing effect
Drug mechanisms: T-cell apoptosis¹
- Mediated by of Rac1 activation: Binding of azathioprine-generated 6-thioguanine triphosphate to Rac1 instead of GTP
- Activation of Rac1 target genes (MEK, NF-κB, bcl-x_L): Suppressed by azathioprine
- Requires costimulation with CD28
- Overall: Converts costimulatory signal to mitochondrial pathway of apoptosis

Cyclosporine A

Cyclosporine A

Indications
- Functionally significant disability
- Long-term immunosuppression
- Especially when prednisone cannot be used or is ineffective
- When relatively rapid response (Months) is desired
- Disease features mediated by T-cells
- Specific neuromuscular disorders
  - Myasthenia gravis
  - Chronic immune demyelinating polyneuropathy (CIDP)
  - ? Some inflammatory myopathies
Usual doses
Initial: 2.0 to 2.5 mg/kg bid
Long term maintenance: Lowest effective dose
- Serum level
  - 50 to 150 ng/ml
  - Often effective below "therapeutic range"
Monitor
- Renal function
- Blood pressure
- Blood level: Draw exactly 12 hours after previous dose
Advantages
- Short onset of action (1 to 3 months)
- Few side effects at low doses
Disadvantages
- Serious side effects: Most are dose related
  - Nephrotoxicity
  - ?Increased risk of malignancy
  - Teratogenic
- Many drug interactions
  - Especially avoid: NSAIDs; Amphotericin B and nephrotoxic drugs
- High cost
- Needs serum level monitoring
  - Trough levels: Obtain 12 hours after last dose
Mechanism of action
- via Calcineurin
  - Normally activated by stimulation of T-cell receptor-associated CD3 complex
  - Inhibited by Cyclosporine and Tacrolimus
- Final pathway: Reduced synthesis of NFAT & IL-2

Methotrexate

Methotrexate

Indications
- Functionally significant disability
- Long-term immunosuppression
- Especially when prednisone cannot be used or is ineffective
- When relatively rapid response (Months) is desired
- Disease features mediated by T-cells
- Specific neuromuscular disorders
  - Inflammatory myopathies
  - Chronic immune demyelinating polyneuropathy (CIDP)
  - Myasthenia gravis
  - Vasculitis: Adjunctive therapy with prednisone
Usual doses
7.5 mg to 25 mg as single, or 2 divided doses, 1 day each week
- Long term: Continue for > 1 to 2 years after remission
- Increased efficacy in early rheumatoid arthritis with concurrent Doxycycline (20 mg twice daily) treatment³
  - Possibly related to anti-metalloproteinase (MMP-1, MMP-8 & MMP-11) effects of doxycycline
Monitor
- CBC
- Liver function
- Renal function: Drug is excreted via kidneys
- Chest X-ray: Before treatment & yearly
Advantages
- Short onset of action (1 to 3 months)
- Few side effects at low doses
Disadvantages:
- Serious side effects: Uncommon in NM disease Rx
  - Gastrointestinal intolerance
    - Nausea
    - Stomatitis
    - Diarrhea
    - Hepatotoxicity
      - Fibrosis
      - Elevated liver enzymes (AST)
    - More common with
      - Methylenetetrahydrofolate reductase (MTHFR) mutation (C677T)
      - Longer drug use
      - Administration of folic acid
  - Pneumonitis
    - Interstitial fibrosis
    - Symptoms: Cough; Dyspnea
    - More common with concurrent Gold, Penicillamine, Infliximab or Sulfasalazine
    - Monitor chest x-ray yearly
  - Bone marrow suppression
  - CNS
    - Symptoms: Headache; Lethargy
    - More common with
      - Younger patients
      - DMARD administration: Sulfasalazine; Hydroxychloroquine; Leflunomide
  - Teratogenicity
  - Genotypes (Polymorphisms) of folate-dependent enzymes associated with presence & types of toxicity²
    - Central nervous system: MTHFR (677TT); Serine hydroxymethyltransferase (SHMT1; 1420CC)
    - Gastrointestinal: Amino imidazole ribonucleotide transformylase (ATIC; 347GG)
    - Alopecia: Thymidylate synthase (TSER*2/*2 (2 28-bp repeats in promoter)); SHMT1 1420CC
    - More than one polymorphism: Risk of side effects higher than with single polymorphism
- Drug interactions: Many
  - Especially avoid: NSAIDs
  - Drugs displacing methotrexate from plasma proteins
    - Chloramphenicol, Sulfonylureas, Phenytoin, Salicylates, Sulfonamides, Tetracyclines
  - Drugs causing renal impairment: Amphotericin B, Aminoglycosides, cis-platin
- High cost

Cyclophosphamide

Cyclophosphamide

Indications
- Functionally severe disability
- Long-term immunosuppression with failure of other immunomodulating treatments
- When relatively rapid response (Months) is desired
- Disease features associated with serum IgM autoantibodies
- Specific neuromuscular disorders
  - Demyelinating neuropathies with IgM antibodies: Use IV cyclophosphamide + Plasma exchange
    - Multifocal motor neuropathy
    - Neuropathy with anti-MAG antibodies
  - Vasculitis: Adjunctive therapy with corticosteroids
  - Other refractory immune disorders with poor prognosis
Usual doses: Intravenous preferred; Often preceded by plasma exchange
- Intravenous: 1 gram/M² monthly x 6
Oral: 2.0 to 2.5 mg/kg/day; Single dose each morning
Monitor
- CBC; Platelets
- Urine
- Total drug dose: Lifetime > 75 gm strongly associated with increased risk of neoplasm
- Titers of autoantibodies (IgM vs MAG or GM1 ganglioside)
Advantages
- Short onset of action (1 to 6 months)
- May be effective when other immunosuppressive medications are not
Disadvantages:
- Side effects
  - Gastrointestinal intolerance: Nausea/Vomiting
  - Bone marrow suppression
  - Neoplasia: Lymphoma; Myeloproliferative; Bladder
  - Cystitis: Hemorrhagic
  - Infertility
  - Teratogenicity
  - Alopecia
- Drug interactions
  - Prolonged NMJ blocking by succinylcholine
  - Toxicity increased from cocaine
  - Drugs altering hepatic metabolism or cytochrome P-450

Mycophenolate mofetil (CellCept)

Indications
- Systemic immune disorders
- Long-term immunotherapy
- Replacement for more toxic drugs: Corticosteroids; Cyclophosphamide
Usual doses
- 2000 to 3000 mg/day in two or three divided doses
- Serum levels unpredictable: May vary up to 10-fold in individuals on same daily dose
- Renal insufficiency: Reduce dosage to avoid toxicity
- Higher doses may be required in African Americans
Monitor
- CBC: Every one (initially) to 8 weeks (with stable dose)
Advantages
- Less toxicity than azathioprine, cyclophosphamide or corticosteroids
- May be more effective than azathioprine
Disadvantages
- Relativley slow onset of action
- High cost
- Possible increased risk of infection
Drug mechanisms
- Inhibitor of ionosine monophosphate dehydrogenase (IMPDH)
  - Blocks type II isoform in activated lymphocytes
  - Inhibits de novo purine synthesis
- Inhibits: T- & B-lymphocyte proliferation; Mixed lymphocyte reaction
- Induces apoptosis of activated T- lymphocytes
  - Eliminates clones of cells responding to antigenic stimulation
- Preferentially suppresses primary versus secondary antibody responses
- Suppresses expression of vascular adhesion molecules: Reduces lymphocyte trafficking into inflamed tissues
- Suppresses induction of inducible form of nitric oxide synthetase

Plasma Exchange

Indications
- Acutely ill patients
  - Especially with respiratory or bulbar involvement
  - Not usually for long-term treatment
- ? Potentiation of intravenous cyclophosphamide Rx
- Specific neuromuscular disorders
Dose
- Sole therapy: 5 exchanges over 8 to 10 days
- Preceding cyclophosphamide: 2 exchanges on consecutive days
Advantages
- Very short onset of action (3 to 10 days)
- Few long term side effects
Disadvantages
- Requires specialized equipment & personnel
- Complications more frequent in elderly
- High cost
- Benefit only short-term (weeks)
- More side effects than human immune globulin

Human Immune Globulin

Possible mechanisms of action
- Serum complement levels: Reduced ;
- F_c receptor: Bindign & Blockade
- Idiotype binding & blocking
Indications
- Acutely ill patient
- Occasionally for long-term treatment when other therapies not effective
- Specific neuromuscular disorders
  - Demyelinating neuropathies with conduction block
    - Chronic immune demyelinating polyneuropathy (CIDP)
    - Multifocal motor neuropathy
  - Dermatomyositis
  - Guillain-Barré
  - Myasthenia gravis
Dose: 2 grams/kg (over 2 to 5 days)
Advantages
- Easily administered: Widely available; Dosage over 2 days
- Serious side effects rare
- Short onset of action
- Fewer side effects than plasma exchange
Disadvantages
- Benefits not well demonstrated
- Very high cost
- Benefit only short-term unless repeat treatments administered

Rituxan

Drug mechanism: Monoclonal antibody against CD20 antigen on B-cells
New dose schedule
- Initial: 375 mg/M² intravenous, Weekly x 2
- Maintenance: 375 mg/M² IV every 10 weeks
Indications (Not FDA approved)
- Neuropathy with associated IgM antibody
  - Multifocal motor neuropathy with IgM anti-GM1 or anti-GalNAc-GD1a antibodies
  - Neuropathy with anti-MAG antibodies
Monitor
- Hematologic: Hematocrit, WBC, platelets; CD3 &aqmp; CD19 cell count
- Titers of autoantibodies (IgM vs MAG or GM1 ganglioside)
Advantages
- Few serious side effects
Disadvantages
- Immunosuppression: Absent B-cells
- Needs repeated treatments for continued efficacy
- No long term experience to define possible side effects
- Side effects: Occasional allergy or anaphylaxis to medication
- Drug interactions: Avoid anti-Hypertensive medication in 12 hours before dose
External link: Genentech/IDEC

References: Internet sites with drug information

PDR: http://www.pdr.net/

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1. J Clin Invest 2003;111:1133-1145
2. Arthritis Rheum 2006;54:607–612
3. Arthritis Rheum 2006;54:621-627

2/20/2006