Myasthenia Gravis: Associated disorders

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Myasthenia Gravis: Other associations

HLA associations
Other antibodies
Pregnancy
Striational antibodies
Systemic disorders
Thymus
Size changes
Thymoma

Thymoma in patient with Myasthenia Gravis
Chest X-ray: Right anterior mediastinal mass

Thymoma

Thymoma: General
- Definition: Neoplasm of epithelial cells of thymus
- Location
  - Anterior mediastinum: 90%
  - Most common anterior mediastinal mass in adults (20% to 50%)
- Age
  - Most common in 4th to 6th decades
  - Uncommon in children
- Male = Female
- Prognostic features
  - Invasive (35%): Poorer prognosis
  - Non-Invasive (Encapsulated; 65%): Better prognosis
  - Thymic carcinoma: Poor prognosis
- Treatment
  - Stage 1 (Encapsulated): Tumor resection
  - Stage 2 (Macroscopic invasion into capsule, fat or pleura): Tumor resection, then Irradiation
  - Stage 3 (Macroscopic invasion into neighboring organs)
    - Neoadjuvant Chemotherapy; Tumor resection; Irradiation; Consolidation Chemotherapy
Thymoma: Associated Paraneoplastic syndromes
- Neuromuscular
  - Myasthenia gravis: 30% of Thymomas; Nicotinic AChR antibodies (100%)
  - Isaac's syndrome: Voltage-gated K⁺ channel antibodies
  - Rippling muscle syndrome: Skeletal muscle antibodies
  - Granulomatous myositis
  - Autonomic neuropathy: Ganglionic AChR antibodies
  - Inflammatory myopathy: Skeletal muscle Ca⁺⁺ release channel (Ryanodine receptor) antibodies
- CNS
  - Cerebellar: CV2 syndromes
  - Morvan's fibrillary chorea
  - Collapsin response-mediator protein-5 (CRMP-5) syndromes
  - Encephalopathy
  - Hearing loss
- Hematologic
  - Pure red cell aplasia: 5% to 8% of Thymomas
  - Hypogammaglobulinemia: Acquired; 5% of Thymomas
- Skin
  - Alopecia/Vitiligo
  - Pemphigus
- GI: Pseudo-obstruction
  - Antibody vs 66 kDa rat brain antigen (CV2)
  - Rx pyridostigmine
- Endocrine
  - Hypercalcemia
  - Cushing syndrome
Thymoma: Other associated autoantibodies⁹
- Glutamic acid decarboxylase: 22%; Higher with associated neurological syndromes
- Striational
- Hu (Antineuronal nuclear antibody-type 1 (ANNA-1))
Thymoma types: Lymphoepithelial
- Noninvasive thymoma
  - Almost all are > 25 years old
  - Most common: 5th to 6th decade
  - Calcification in 5-20%
- Invasive thymoma
  - Metastasis to pleura and lungs (6%); rarely extrathoracic
Thymic tumors & MG
- Frequency
  - Thymoma
    - 7% to 15% of MG patients
    - Mostly in MG patients > 30 years
  - MG: Frequency varies with thymoma type
    - Thymomas + MG: Usually composed of cortical cells
    - Other thymomas: Mixed pattern; More undifferentiated malignancy
  - Tumor type relations
    
    Tumor Spread MG
    frequency
    
    Cortical ++ +++
    
    Well differentiated +++ +++
    
    Medullary - +
    
    Mixed - ++
    
    Undifferentiated +++ -
- Anti-AChR antibody (Binding) association
  - Patients with MG and thymoma: Frequency = 95% to 100%
  - Thymoma without clinical MG
    - Other associated neurological disorders: 50%
    - No associated neurologic disorders: 30%
- Muscle pathology: Increased frequency of lymphorrhages
Clinical work-up
- Computed tomography scan of the thorax
  - Should be performed to look for thymoma in MG patients aged 20 and above
- MRI examinations of the chest: More expensive and not clearly superior
Therapeutic implications
- Removal of thymoma should be through trans-sternal approach
- MG may become more difficult to manage when thymoma removed

Tumor	Spread	MG frequency
Cortical	++	+++
Well differentiated	+++	+++
Medullary	-	+
Mixed	-	++
Undifferentiated	+++	-

Thymoma (Anterior mediastinal mass) in patient with Myasthenia Gravis

Thymic size changes

Thymoma
Hyperplasia of thymus
- Overall frequency: Occurs in 60% to 80% of MG patients
- Positive associations
  - Younger age groups (< 40 years)
  - Female > Male 4:1
  - HLA associations
    - B8
    - DR3
  - Anti-AChR antibodies: High titer
  - Chromosomal linkage: MYAS1; 6p21.3 ¹¹
    - Haplotype 8.1: Highest association with 2 copies of the haplotype.
    - Locus also associated with increase in titers of anti-AChR antibodies
    - Locus is near class III & proximal class I
    - Neighboring locus in cis may repress the effects of MYAS1 locus
    - Other locus associated with MG: Class II gene allele, DQA1*0101, interacting with polymorphism of CHRNA1
- Negative associations
  - HLA DR7
  - MuSK antibodies
  - Anti-titin antibodies
- Pathology
  - Corticomedullary junction & medulla with germinal centers
  - B-lymphocytes: Increased frequency; Activated
  - T-lymphocytes
    - Increased frequency: CD4+/CD8- & CD4-/CD8+
    - Reduced frequency: CD4+/CD8+
    - Increased AChR responsive cells
- Therapeutic implication
  - Thymectomy may promote long-term clinical improvement of MG in patients under 50 - 55
- Other immune disorder with thymus hyperplasia
  - Sjögren syndrome: More common with¹⁰
    - Disease duration ≤ 5 years
    - Anti-Scl70 antibodies
Atrophy of thymus: 20%
- Usually > 50 years
- Therapeutic implication
  - Thymectomy less commonly performed after 50 to 55 years
Normal thymus size: Heterogeneous group
- Anti-titin antibodies present in serum
  - HLA DR7: Increased frequency
  - HLA DR3: Decreased frequency
  - Anti-AChR antibodies: Moderate titer
- No anti-titin antibodies
  - HLA DR3: Increased frequency

Anti-striational antibodies

Myasthenia Gravis: Adult-onset
- Age related
  - All MG patients: 30%
  - < 20 years: Rare; Association with graft-versus-host disease
  - > 60 years: 55%
- Thymoma: Frequency of striational antibodies
  - + MG: 75%
  - + MG + Other Neurological syndrome: 87%
  - + Other Neurological syndrome, No MG: 29%
  - No MG or neurological syndrome: 21%
- MG features
  - Greater weakness
  - Myopathic changes on EMG
Progressive rise in titer: May indicate thymoma recurrence
Other disorders
- Autoimmune liver disorders
Target antigens: Varied
- Titin : Antibodies⁴
  - Epitope: Main immunogenic region (MGT-30 peptide)
  - Common
    - MG patients + Thymoma
      - Frequency: 68% to 100%; More common with MG onset > 50 years
      - Most common with epithelial-Predominant thymoma
      - All patients with anti-titin Ab < 50 years of age have thymoma
    - MG without thymoma
      - Age > 60 years: 50% to 90%
      - HLA-DR7
      - Early onset MG: Rare
      - Seronegative MG: Rare or Absent
      - Thymus: No germinal centers
  - Specificity
    - Highest for thymoma in patients < 50 years
    - Higher than CT examination
  - Titers
    - Correlate with severity of MG
    - Reduced after thymectomy
  - Uncommon
    - MG patients 40 to 60 years without thymoma
    - No anti-AChR antibodies
    - Thymus hyperplasia
    - Other autoimmune disorders
  - Disease controls: Mildly elevated titers may occur
  - Healthy controls: Rare (0.4%)
- Ryanodine receptor antibodies⁸
  - Associated with thymoma
    - Frequency in MG + thymoma: 80% to 90%
    - MG without thymoma: Rare; < 10%
    - MG + Myositis
  - Antigenic epitopes more common at
    - C-terminus (AA 5019-5038)
    - C-terminus transmembrane (AA 4997-5017) regions
  - Clinical
    - Occur in patients with more severe MG symptoms
    - Weakness: Non-limb
      - Bulbar
      - Ocular
      - Neck
      - Respiratory
  - Also see
- Actinin

Myasthenia Gravis: Other antibodies

Anti-nuclear antibodies: 20% to 40%; ? more common in MG patients with thymoma.
Anti-thyroid (microsomal & thyroglobulin; 15% to 40%) and anti-parietal cell (10% to 20%)
- Not clearly associated with thymoma
- More common in ocular MG
Smooth muscle: 5% to 10%
Rheumatoid factor: 10% to 40%
Coomb's: 10%
Anti-lymphocyte: 40% to 80%
Anti-platelet: 5% to 50%
Interferon α⁴
- MG + Thymoma: 74%; Increased levels with thymoma recurrence
- Late onset MG without thymoma: 33%
- Early onset MG: 0%
IL12⁴
- MG + Thymoma: 47%%; Increased levels with thymoma recurrence
- Late onset MG without thymoma: 8%
- Early onset MG: 2%
Potassim channel: Kv1.4
- Frequency in MG: 12%
- Associations
  - Bulbar involvement
  - Myasthenic crisis
  - Thymoma
  - Concomitant myocarditis and/or myositis

Myasthenia Gravis & Systemic disorders

Thyroid: Disorders in ~ 15% of MG patients
- Hyperthyroidism more common than hypothyroidism
- Both can exacerbate MG
- Thyroid testing: Always indicated in MG workup
Other autoimmune disorders: Increased incidence
- Rheumatoid arthritis
- Lupus erythematosus
- Polymyositis
- Pernicious anemia
- Laboratory screening: As indicated by signs in individual patients
Bone marow transplantation: Graft-vs Host disease (GVHD)
- Prior history of cGVHD
- Onset of MG: Associated with discontinuation of immunosuppressive drugs
- Anti-AChR antibodies: Present
- OX40⁺CD4⁺ T cells: Increased
- Treatment: Prednisone; Immunosuppression⁶
Infections
- Ongoing MG: Exacerbation of symptoms during active infection
- HIV associations
  - Few cases reported
  - Onset: Early in disease course; CD4 count > 200
  - Disease course: May be transient (Months) with spontaneous remission
  - AChR antibody: Positive in 50%
  - HIV may be associated with thymitis with B-cell germinal centers
Drug treatment: Numerous medications may exacerbate MG
- With antibiotics
  - Use as indicated for specific infection
  - Monitor closely
  - Change if increasing weakness
Pregnancy & MG³
- Short term
  - Course of MG during pregnancy: Unpredictable; 20% Worse, 20% Improved, 60% No change
  - Exacerbations most common in 1st trimester & 1st post-partum month
  - No correlation between severity of MG before pregnancy & course during pregnancy
- Long term: No effect on MG prognosis
- Effect of pregnancy on child
  - Associated with: Neonatal MG; Recurrent Congenital Arthrogryposis
  - No increase in spontaneous abortion
  - ? More perinatal deaths with fetal anomalies
- Treatment
  - Safe: Anticholinesterase; Corticosteroids; Plasma Exchange; Human immune globulin
  - Minor risk (Use with caution): Azathioprine has no clear teratogenicity;
  - Some risk (Use with caution)
    - Cyclosporine A: Associated with more spontaneous abortions & preteerm deliveries
  - Higher risk: Methotrexate should probably not be used during pregnancy
- Breast feeding: Treatment
  - Safe
    - Anticholinesterase: High doses may produce gastrointestinal disorders in neonate
    - Corticosteroids; Plasma Exchange; Imunoglobulin
  - Not safe: Immunosuppressants may produce immunosuppression in neonate

Acquired MG: Genetic Associations^1,
2

Familial recurrence risk

Frequency in relatives of patients: 0.4 to 4%
- Prevalence in Caucasians without family history: 1/10⁴
Pattern of inheritance: Complex

Acetylcholine receptor

AChR α subunit: HB*14
- Dinucleotide CA-repeat
- Located in 1st intron of gene
- Present in ~ 20% of antibody + MG patients
Stronger association when HLA: DQA1*0101 ± DQA1*0501

HLA: Myasthenia Gravis associations⁷

General: HLA-DR3 B8 A1 extended ancestral haplotype
- Associated with MG subtype
  - Early onset (Young adult)
  - Presentation with thymus hyperplasia
- Same haplotype associated with other human autoimmune diseases
  - Systemic lupus erythematosus
  - Celiac disease
  - Diabetes, type I
  - Autoimmune thyroiditis
- ? Mechanism: Non antigen-specific immune dysregulation
HLA class I alleles
- B8: Association in Blacks
- Bw46: Association in Chinese
- A1
DR: Class II
- DR3: + MG association⁵
  - Female predominance (80%)
  - Early onset: < 40 years
  - Thymic hyperplasia
  - Anti-AChR antibodies: Intermediate or high titers
- DR7
  - Anti-Titin antibodies
  - Late onset age
  - Negative association: Thymic hyperplasia; Thymoma
- DR9
  - Thymic hyperplasia + MG
  - Geography: Japan & China
  - Mild MG: Ocular symptoms
- DR16: MG + Thymic hyperplasia
- DR52a (DRB3*0101)
  - Restricting class allele for T-cell recognition of e-AChR epitope (amino acids 201-219)
- No DR association: Thymoma
DQ: Class II
- DQA1 Domain 1: - All MG
- DQB1 Domain 2: - Early onset; Thymic hyperplasia
- DQB1 Domain 3: + All MG
- DQB1: Position 57 amino acids
  - Alanine
    - +: Early onset MG
  - Valine
    - -: Early onset MG & Thymic hyperplasia
    - +: Thymoma
  - Asparagine & Serine: No MG associations
  - Aspartate: Protective effect against insulin-dependent diabetes mellitus (IDDM)
- External link: DQ
Other HLA-linked genes associated with MG
- Complement C4
- TNFα
- MYAS1 locus: Telomeric to class II gene region

Tumor necrosis factors α & β

Titin antibody: Homozygous for TNFA*T1 & TNFB*2 alleles
Early-onset MG & No titin antibodies: TNFA*T2 & TNFB*1 alleles

HLA molecules

Products of genes from major histocompatibility complex (MHC): Chromosome 6
MHC class I molecules
- Present on all nucleated cells
- HLA-A , B , C
MHC class II molecules
- Present on mononuclear cells
- HLA-DN , DP , DQ , DR

HLA disease associations
HLA-B27	Reiter's Ankylosing spondylitis
HLA-DR4	Rheumatoid arthritis Sjögren's syndrome Giant Cell Arteritis Lyme arthritis
HLA-DR3	SLE Dermatomyositis CREST
HLA-B8	Myasthenia Gravis Grave's disease Chronic active hepatitis
HLA-A3	Multiple sclerosis Hemochromatosis

Return to Myasthenia

References
1. J Neuroimmunol 1996;65:125-131
2. J Autoimmunity 1997;10:407-413
3. Neurology 1999;52:447-452
4. Neurology 2001;57:1579-1582, Neurology 2002;59:92�98
5. Neurology 2001;57:1555-1560
6. Eur J Haematol 2002;69:318�320
7. J Autoimmunity 2003;21:105�110
8. Neurology 2004;62:1894�1896, Arch Neurol 2000;57:527-531, Eur J Neurol 2007;14:617-620
9. Clin Cancer Res 2004;10:7270�7275
10. Rheumatology (Oxford) 2005; Sep 27
11. Proc Natl Acad Sci U S A. 2004;101:15464-15469

7/2/2008