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Myasthenia Gravis: Other associations

Genetic   AChR   HLA   PTPN22   TNF Inflammatory myopathy   BCIM   Myositis 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 Treatments 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 (PNS) 23 General 50% of thymomas present with paraneoplastic syndrome 33% of thymoma PNS have > 1 disorder Onset: Before, or After, thymoma treatment Thymoma survival: Better if PNS resolves Neuromuscular Myasthenia gravis Isaac's syndrome: Voltage-gated K+ channel antibodies Rippling muscle syndrome: Skeletal muscle antibodies Autonomic neuropathy Intestinal pseudo-obstruction Serum: Ganglionic AChR antibodies Immune myopathy Myositis Granulomatous myositis Ryanodine receptor Ab CNS Cerebellar: CV2 syndromes Morvan's fibrillary chorea Collapsin response-mediator protein-5 (CRMP-5) syndromes Encephalopathy Limbic encephalitis Hearing loss Hematologic Pure red cell aplasia: 5% to 8% of Thymomas Hypogammaglobulinemia (Good syndrome) Acquired Frequency: 3% to 6% of Thymomas Associations: Adult-onset immunodeficiency B cells: Low or absent Defects in cell-mediated immunity Inverted CD4/CD8(+) T-cell ratio Infections: CMV Lymphocytosis Myocarditis Skin Alopecia/Vitiligo Pemphigus Lichen planus Candida GI: Pseudo-obstruction Antibody vs 66 kDa rat brain antigen (CV2) Rx pyridostigmine Endocrine Hypercalcemia Cushing syndrome Other immune Lupus Nephrotic syndrome Thymoma: Associated autoantibodies 9 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% Striational: Titin Ryanodine receptor KCNA4 Glutamic acid decarboxylase Frequency: 22% Higher with associated neurological syndromes Hu (Antineuronal nuclear antibody-type 1 (ANNA-1)) CASPR2 DCC Lgi1 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 & Myasthenia gravis Frequency Most common thymoma paraneoplastic syndrome 25% to 40% of Thymomas Serum: Nicotinic AChR antibodies (99%) 15 Thymoma in MG 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 +++ - Myasthenia gravis + Thymoma: Clinical 25 Similar to other AChR-Ab+ MG May be: More Severe; Difficult to treat; Worse prognosis May be associated with: Other paraneoplastic disorders Thymoma recurrence: May be related to transient MG worsening Non-resectable thymoma: MG may be more severe No HLA association identified MG Prognosis better 24 AChR antibody: Positive Thymic follicular hyperplasia Non-recurent neoplasm No relation to tymoma tissue subtype Muscle pathology: Increased frequency of lymphorrhages Clinical work-up Computed tomography scan of the thorax Performed to look for thymoma in MG patients aged ≥ 20 years MRI examinations of the chest More expensive Not clearly superior Therapeutic implications Removal of thymoma: Trans-sternal approach MG: ? More difficult to manage after thymoma removed

Thymoma (Anterior mediastinal mass) in patient with Myasthenia Gravis    Bell 1917

Thymus: Size & Other 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
    • Ectopic germinal centers: Increased numbers ²⁹
      • With AChR Ab in serum
      • Better outcome at 2 years after thymectomy
    • B-lymphocytes
      • Increased frequency
      • Activated
      • 2 patterns of distribution
        • B-cell follicles with germinal centers (Follicular hyperplasia)
        • Distributed throughout medullary parenchyma (Diffuse hyperplasia)
    • T-lymphocytes
      • Increased frequency: CD4+/CD8- & CD4-/CD8+
      • Reduced frequency: CD4+/CD8+
      • Increased AChR responsive or specific cells
    • Plasma cells: Secrete anti-AChR antibodies
    • Epstein-Barr Virus¹⁴
      • Commonly present in MG thymus: Large or Involuted
  • 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 ¹⁶

• 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
    • AChR antibody +
• Progressive rise in titer: May indicate thymoma recurrence
• Other disorders
  • ICI-related myopathies
  • Autoimmune liver disorders
• Target antigens: Varied
  • May be several antigenic targets in individual patients
  • Titin : Antibodies ⁴
    • Epitope
      • Main immunogenic region (MGT-30 peptide)
      • Near A/I-band junction
    • Genetic association
      • PTPN22 : C1858T polymorphism
    • Clinical: Common syndromes
      • General MG ³⁰
        • Frequency: 40%
        • More common in
          • Older MG patients
          • Milder MG
        • Association: Myocarditis
        • No clear association: Thymoma
        • Specificity
          • Highest for thymoma in patients < 50 years
          • Higher than CT examination
        • Titers
          • Correlate with severity of MG
          • Reduced after thymectomy
      • MG patients + Thymoma
        • Frequency: 68% to 100%; More common with MG onset > 50 years
        • Most common with epithelial-Predominant thymoma
        • Patients with anti-titin Ab < 50 years of age commonly have thymoma
      • MG without thymoma
        • Age > 60 years: 50% to 90%
        • HLA-DR7
        • Early onset MG: Rare
        • Seronegative MG: Rare to 13%
        • Thymus: No germinal centers
      • ICI-related myopathies
      • Other neurologic disease: 4%
    • Uncommon
      • MG patients 40 to 60 years without thymoma
      • No anti-AChR antibodies
      • Thymus hyperplasia
      • Other autoimmune disorders
    • Other
      • Disease controls: Mildly elevated titers may occur
      • Healthy controls: Rare (0.4%)
  • Ryanodine receptor antibodies ⁸
    • All MG: 13% to 38%
    • 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
      • Granulomatous myopathy
      • Malignant hyperthermia
      • Central core disease
  • Kv1.4
  • Actinin

Myasthenia Gravis: Other antibodies

• Anti-Nuclear antibodies
  • Frequency: 20% to 40%
  • ? More common in MG patients with thymoma
• Anti-Thyroid: Microsomal & Thyroglobulin (15% to 40%); Anti-parietal cell (10% to 20%)
  • Not clearly associated with thymoma
  • More common in ocular MG
• Smooth muscle: 5% to 10%
• Acetylcholinesterase (AChE) ¹³
  • Common in MG (48%)
  • Most frequent in: Ocular MG
  • More frequent with thyroglobulin antibodies
  • Other immune disorders: Systemic lupus erythematosus, Rheumatoid arthritis, Graves' disease + Thyroid autoantibodies
• Rheumatoid factor: 10% to 40%
• Coomb's: 10%
• Anti-Lymphocyte: 40% to 80%
• Anti-Platelet: 5% to 50%
• Interferon α ⁴
  • MG + Thymoma: 74%; Increased levels with thymoma recurrence
  • Late onset MG without thymoma: 33%
  • Early onset MG: 0%
• LRP-4
• Agrin
• Collagen XIII
• IL12 ⁴
  • MG + Thymoma: 47%%; Increased levels with thymoma recurrence
  • Late onset MG without thymoma: 8%
  • Early onset MG: 2%
• CRMP-5/CV-2
• Potassium channel antibody: Kv1.4 (KCNA4)
  • Frequency
    • MG: 12%-15%
    • More common in
      • Younger MG patients: Mean age 49 years
      • Checkpoint inhibitor-related MG
  • Antigenic eptope
    • Conformational
    • Striational
  • Associations
    • More severe MG
    • Bulbar involvement
    • Myasthenic crisis
    • Thymoma
    • Concomitant
      • Myocarditis
        • Arrhythmias: Lethal
        • Onset: 1 to 18 years after MG onset
      • Myositis
    • Treatment response: To calcineurin inhibitors (Cyclosporine; Tacrolimus)
• TRPC3: More common with thymoma
• Epstein-Barr virus, Type 1 nuclear antigen (EBNA-1) ¹⁷
  • IgG type
  • Associated with MG, onset < 50 years (31%)
    • OR 3.1 vs older MG
    • 2x more frequent than controls
  • No relation to thymus pathology
  • Anti-titin antibodies: Reduced frequency
  • EB virus infection: Develop 2 to 4 months after; Persist life-long
  • EB virus DNA found in hyperplastic thymus
  • Anti-EBNA-1 antibodies also risk factor: Multiple sclerosis; Rheumatoid arthritis; SLE
• Nuclear receptor interaction protein (NRIP; DCAF6) ²⁶
  • NRIP protein
    • NMJs
      • Co-localizes with AChRs, Rapsyn & α-actinin 2 (ACTN2)
      • Stabilizes AChR, Rapsyn, ACTN2 complex
    • Interacts with: Androgen & Glucocorticoid receptors
  • NRIP serum antibody
    • Antibody type: IgG₁ most common
    • Antibody binding site: IQ motif on NRIP
    • Frequency
      • Autoimmune MG: 14%
      • Controls: Up to 30%
    • Clinical: More severe disease in AChR Ab+ MG, especially with higher anti-NRIP titers

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
  • Autoimmune thyroid disease (8% of MG) ¹⁹
    • Graves disease: Most common
    • MG onset: Younger
    • Female
    • MG type: Ocular or Mild; Thymic hyperplasia
• Other autoimmune disorders: Increased incidence
  • Rheumatoid arthritis
  • Lupus erythematosus ²⁰
    • Females
    • Onset age: Mean 4th decade; 18 to 72 years
    • AChR Ab+: 94%
    • SLE features
      • Arthritis (88%)
      • Older onset & Less severe than average
      • Antibodies: Anticardiolipin; Lupus anticoagulant
  • Inflammatory myopathy: BCIM
  • Pernicious anemia
  • Neuromyelitis optica ¹⁸
    • With aquaporin 4 (AQP4) antibody (85%)
    • After > Before MG onset (96%)
    • Females
    • MG Onset: Juvenile or Young adult
  • Sjögren ³¹
  • 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
      • Improves with progressive immunodeficiency
    • AChR antibody: Positive in 50%, often low titer
    • Thymus
      • Hyperplasia unusual
      • HIV may be associated with thymitis with B-cell germinal centers
  • West Nile virus
    • Myasthenia gravis (AChR Ab+) onsets 3 to 7 months after WNV infection
• Drug treatment
  • Numerous medications may exacerbate MG
  • With Antibiotics
    • Use as indicated for specific infection
    • Monitor closely
    • Change if increasing weakness
  • Checkpoint inhibitors
• Pregnancy & MG ³
  • Short term
    • Course of MG during pregnancy: Unpredictable
      • Worse: 20% to 33%
      • Improved: 20% to 30%
      • No change: 40% to 60%
    • Exacerbations
      • Most common: 1st or 2nd trimester & 1st post-partum month
      • More risk: Infections; Shorter MG disease history: RNS decrement; More severe MG
    • Correlation between severity of MG before pregnancy & course during pregnancy: Some studies
  • Long term: No effect on MG prognosis
  • Effect of pregnancy on child
    • Associated with
      • Neonatal MG (Transient)
      • Recurrent Congenital Arthrogryposis
    • No increase in spontaneous abortion
    • ? More perinatal deaths with fetal anomalies
  • Pregnancy
    • C-section: Increased frequency
    • Preterm premature rupture of membranes: Increased in some studies
  • 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}

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

• 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

• General: HLA-DR3 B08 A1 extended ancestral haplotype
  • HLA-B*08 (rs7750641): Main risk allele
  • Associated with MG subtype
    • Early onset (Young adult)
    • Females
    • 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
  • DRB1*16: Positive association
  • DRB1*0701: Negative association
  • 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; Thymoma-related in Asians
  • 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
• TNFRSF11A
• Agrin ²⁸
• Protein tyrosine phosphatase, non-receptor type 22 (PTPN22; rs2476601) ¹²
  • Actions
    • Inhibits T-cell activation
    • Inhibits interleukin-2 (IL-2) production
  • PTPN22^{gain-of-function}+1858T(+) (C1858T polymorphism) genotypes: Predispose to multiple autoimmune diseases
    • MG associations
      • Early-onset (non-thymomatous) myasthenia gravis (MG)
      • German Caucasians: Thymoma-associated MG
      • Anti-titin antibodies
    • Other disease associations
      • IIM susceptibility
      • GPA susceptibility
    • Mechanism: ? Impedes central tolerance induction
• T-cell regulation: Late onset MG
  • Galectin-1 (LGALS1) promoter region
  • CTLA4 (CTLA-4/CD152 membrane receptor)
    • Expression: Low in CD4+ T-cells
    • +49A/G coding variant
      • Thymoma-related MG
      • +49G(+) genotype: More frequent with Late onset MG (> 60 years)
    • SNPs at -1772T/C & -1661A/G upstream of CTLA-4: Swedish MG association
    • Ipilimumab & other checkpoint inhibitors
      • Binds to CTLA4
      • Associated with appearance of immune disorders
    • Other disease susceptibility
      • GPA
      • Autoimmune lymphoproliferative syndrome, type V : Dominant
      • Celiac disease
      • Diabetes mellitus, insulin-dependent, 12
      • Hashimoto thyroiditis : Dominant
      • Systemic lupus erythematosus : Dominant
  • CD28
• Regulators of toll-like receptor 4 signalling: Early onset MG
  • ORMDL3
  • GSDMB
  • TRAF3
  • TNFAIP3-interacting protein 1 (TNIP1)
    • Lower levels in MG with thymoma
    • Levels increased after thymectomy
• S100P
• GAB2
• NFKBIA
• PPP1R15A
• Histamine N-Methyltransferase (HNMT) ²¹
  • A allele of A939G SNP: Over-represented in MG with anti-AchR & anti-Titin antibodies
  • G allele carrier + Wild-type C314C homozygosity: Protective against MG & Development of anti-AchR antibodies
• AIRE ²²
  • MG susceptibility: Rs3761389 polymorphism in Chinese patients (OR = 1.3)

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