Immunosuppression

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IMMUNOMODULATING THERAPIES FOR NEUROMUSCULAR DISORDERS

Overview
Medications
Treatment strategies

Azathioprine
Corticosteroids
Intermittent dosing
Cyclophosphamide
Cyclosporine A
Intravenous immunoglobulin
Methotrexate
Mycophenolate mofetil
Plasma exchange
Rituximab
Tacrolimus

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.
- Tacrolimus: : 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

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

Corticosteroid dosages: Comparison
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 overall treatment strategy
- Start at high dose then taper
- Exception: Myasthenia gravis
  - Start at lower dose: 10 mg to 20 qd
  - Then gradually increase up to 50 mg qd
  - With respiratory or bulbar symptoms
    - Pretreat with plasma exchange: Reduces risk of increased weakness associated with corticosteroids
- 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
Prednisone: Daily; By mouth
- Starting dosages
  - Adults: 50 mg to 100 mg per day
  - Children: 1 mg/kg/day
  - Single daily dose in the morning
- Maintenance
Corticosteroids: Intermittent dosing regimens
- General principles
  - Efficacy
    - Similar to more frequent corticosteroid dosing regimens ^6, ^7, ⁸
    - Usual minimum dosing frequency for specific disorders
      - CIDP: 2 to 6 weeks
      - Vasculopathic neuropathies: 2 to 6 weeks
      - Myasthenia gravis: Once or twice weekly
      - Duchenne Muscular Dystrophy: Weekly
      - Immune & Inflammatory myopathies: Daily to Weekly
  - Side effects: Reduced
    - Compared to: Daily dosing corticosteroid regimens
    - May reduce chronic corticosteroid side effects to levels similar to those occurring with IVIg
    - May eliminate need for toxic "Steroid sparing drugs"
    - Specific side effects likely reduced
      - Cushingoid faces
      - Growth retardation in children: Growth of 1"/year more than with daily dosing
      - Body mass index
      - Sleeplessness
      - Irritability
      - Glucose intolerance
  - Cost saving vs Chronic IVIg treatment ⁹
    - $25,000 to $100,000 per patient per year
    - ≥ $650,000 per quality adjusted life year (QALY)
- Solumedrol (Methylprednisolone) ⁸
  - Start: 1 gram iv daily for 3 to 5 days
  - Maintenance & Tapering of dose
    - Start at 1 gm/week iv for 1 month
    - Then 1 gm every 2 weeks for 2 months
    - Taper further by: Increased time between doses; Reduced total dose
    - Change to: Oral corticosteroid administration
- Dexamethasone, Oral: for CIDP ⁶
  - Total dose: 160 mg every 4 weeks
  - Dosage schedule: 40 mg a day for 4 consecutive days
- Prednisone: for Duchenne Muscular Dystrophy ⁷
  - Total weekly dose: 5 to 10 mg/kg
  - Dosage schedule: On weekends; Half on Friday night & Half on Saturday night
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%)
- Side effects
  - Many long-term: Especially with daily, or multiple daily, dosing
  - Fewer with intermittent corticosteroid dosage
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 & Associations
- Pretreatment: Thiopurine S-Methyltransferase (TPMT) ¹¹
  - TPMT deficiency: Reduced azathioprine metabolism; Bone marrow toxicity
- Chronic: Hematocrit, WBC & platelets; Liver function
- Other association: NUDT15 polymorphisms ¹²
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 apoptosis ¹
- 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
- Associated myopathies
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) treatment ³
  - 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 toxicity ²
    - 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
  - MTX: Intrathecal administration
    - Lumbosacral polyradiculopathy ¹³
      - Location: Especially ventral roots
      - Clinical
        
        Onset time: 10 to 40 days after treatment
        
        Weakness: Legs; Paraplegia
        Urinary retention
        Tendon reflexes: Absent
        Sensory loss: May be thoracic level
        Prognosis: Poor
      - Laboratory
        
        EMG: Motor radiculopathy; Absent F-waves, CMAPs small amplitude
        CSF: High or Normal protein
        
        MRI: Ventral root thickening with enhancement
- 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
- Myasthenia gravis exacerbation
  - More cost effective than IVIg for patients with BMI > 15.7 kg/M² ¹⁰
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

Rituximab

Drug mechanism: Monoclonal antibody against CD20 antigen on B-cells
Dose schedule
- Initial: 375 mg/M² intravenous, Weekly x 2
- Maintenance: 375 mg/M² IV every 10 weeks
- Other dose: 750 mg/M² IV has also been used ⁵
Neuromuscular Indications (Not FDA approved)
- Neuropathy with associated IgM antibody: 2 year treatment
  - Multifocal motor neuropathy with IgM anti-GM1 or anti-GalNAc-GD1a antibodies
  - Neuropathy with anti-MAG antibodies
- Immune myopathy
  - Myopathy with SRP antibodies: 2 year treatment
- Myasthenia gravis syndrome
  - Myasthenia gravis with anti-MuSK antibodies: 6 month treatment & after relapse
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
- May need repeated treatments for continued or optimal efficacy
- Side effects
  - Occasional allergy or anaphylaxis to medication
  - Infections
    - Risk increased ⁴
      - Chronic lung or cardiac disease
      - Systemic involvement
      - Low serum IgG levels
    - PML: Reported for patients on multiple immunosuppressants
- Drug interactions: Avoid anti-Hypertensive medication in 12 hours before dose
External link: Genentech/biogen IDEC

References: Internet sites with drug information

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

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11/24/2022