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Myasthenia Gravis: Other associations

Epidemiology Genetic   AChR   HLA   PTPN22   TNF Inflammatory myopathy   BCIM   Myositis Other antibodies Pregnancy Antibodies   Striational   Other 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: Children; MG onset > 65 years 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 Neuromyotonia (20% with thymoma) Thymoma-associated: Often also have MG 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 Common: Thymoma + MG & Late onset MG Uncommon: Young-onset MG Ryanodine receptor Thymoma + MG > Thymoma- MG Cytokines IL12 INFα Neutralizing type I interferons General frequencies MG: 30% MG + Thymoma: 70% Thymoma only: 40% Antibodies: IFN-α2 & IFN-ω; ≥ 10 ng/mL; Neutralizing Risk: Hypoxemic COVID-19 pneumonia: High risk (OR 12.7 ) 37 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 35 Frequency MG: Most common thymoma paraneoplastic syndrome MG in 20% to 40% of Thymomas Serum Nicotinic AChR antibodies 15 MG + Thymoma: (99%) Thymoma without symptomatic MG: 30% 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 A: Medullary (Spindle cell) - + (17%) AB: Mixed - ++ (18%) B1: Lymphocyte-rich ++ +++ (44%) B2: Cortical ++ +++ (54%) B3: Well differentiated (Squamoid) +++ +++ (50%) Thymic carcinoma +++ - Myasthenia gravis + Thymoma: Clinical 25 General: Similar to other AChR-Ab+ MG Differences vs other AChR-Ab+ MG: May be More Generalized More Severe Difficult to treat Worse prognosis May be associated with: Other paraneoplastic disorders Thymoma recurrence May be associated with MG worsening Risk: Dependent on thymoma pathological stage 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 Modality of choice Contrast-enhanced: If thymomas suspected; Greater diagnostic yield Performed to look for thymoma in MG patients aged ≥ 20 years MRI examinations of the chest More expensive Not clearly superior Utility: Iodine allergy; Renal failure Thymoma features T1 signal: Intermediate T2: Heterogeneity & Variable enhancement High-risk lesions: More heterogeneous Therapeutic implications Removal of thymoma General: Trans-sternal approach Early stage thymoma: Minimally invasive surgery MG ? More difficult to manage after thymoma removed New MG: May appear after thymectomy: ? more in AChR Ab+ patients

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%
        • May develop during disease progression
        • More common in
          • Older MG patients: 7th decade
          • More severe disease
          • AChR Ab+ MG
        • Systemic Associations
          • Myocarditis
          • Thyroid disease: Up to 50%
          • No clear association: Thymoma
            • 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
• Immune disorders related antibodies ³²
  • PM/Scl-100: 5%
  • Ro52: 5%
  • Ku: 4%
  • Rheumatoid factor: 10% to 40%
• Coomb's: 10%
• Anti-Lymphocyte: 40% to 80%
• Anti-Platelet: 5% to 50%
• LRP-4
• Agrin
• Collagen XIII
• Interferons & Cytokines
  • Interferon α ⁴
    • MG + Thymoma: 74%; Increased levels with thymoma recurrence
    • Late onset MG without thymoma: 33%
    • Early onset MG: 0%
  • IL12 ⁴
    • MG + Thymoma: 47%%; Increased levels with thymoma recurrence
    • Late onset MG without thymoma: 8%
    • Early onset MG: 2%
  • Other
• 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 ³⁶

• 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 ³⁴
  • General
    • More risk of other immune disorders: 2 fold increased
      • Females
      • Age ≤ 50 years
    • Disorders
      • Autoimmune thyroiditis
      • Systemic lupus erythematosus
      • Pernicious anemia
  • 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
  • Pericarditis
  • Alopecia
  • Autonomic disorders
  • 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: 19% to 33%
      • Improved: 20% to 30%
      • No change: 40% to 60%
    • Exacerbations
      • Most common: 1st (30%) trimester & 1st post-partum month to 6 - 12 months (27%)
      • More risk: Infections; Shorter MG disease history: RNS decrement; More severe MG
      • May be related to patient refusal of treatment
    • 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/Delivery
    • Women may tend to conceive during periods of relative disease stability
    • C-section: Increased frequency
    • Preterm premature rupture of membranes: Increased in some studies
  • Treatment
    • Safe medications: 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/Contraindicated: Methotrexate; Mycophenolate mofetil
  • 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 (CHRNA1)
  • 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
  • rs35274388: Overlaps promoter region; European populations
  • Also see: Hereditary MG
• CHRNB1
  • rs4151121: Late onset AChR Ab+ MG; European populations
  • Also see: Hereditary MG

• 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
• Japan ⁷
  • HLA-DRB1: Late onset generalized MG
  • HLA-A: Early onset generalized MG
  • TERT lead variant rs2736099: MG + Poor treatment response
• 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