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Myopathies & NMJ Disorders: Antibodies & Complement

General topics Antibodies   ANCA   Cytoplasmic   DNA   Myositis-Overlap   Myositis-Specific   Nuclear   Nucleolar   Ribonucleoproteins   Striational   tRNA synthetases   Types Complement Connective tissue disorders Lambert-Eaton myasthenia M-protein   Amyloid: Light chain   Anti-Decorin myopathy: IgM   Scleromyxedema: IgG Myasthenia gravis Neuropathy Scleroderma

Specific antibodies 56 kD RNP Acetylcholine receptor CADM-140 Centromere Double-stranded DNA FHL-1 Fibrillarin Fibroblast Giantin Histones Jo-1 Ku MGT-30 Mi-2 Nucleosome p140 p155 (TIF1γ) Phospholipid PM-Scl Rheumatoid factors RNP   Nuclear     U1-nRNP     U2-nRNP     U3-RNP   Ribosomal Signal Recognition Particle Sm SS-56 SSA (Ro) SSB (La) tRNA Synthetase

Normal IgG

• Anti-Acetylcholine Receptor (IgG)
• MuSK (IgG)
• Anti-Striational (IgG): With Thymoma
• Other

• Anti-P-type Calcium Channel (IgG)

• Clinical features
  • Onset: 7th deacde
  • Weakness
    • Proximal
    • Symmetric
  • Tendon reflexes: Present
  • Course: Slowly progressive to moderate disability
• Laboratory
  • Serum CK: High, ~ 1,000
  • IgMκ M-protein ± Waldenström's macroglobulinemia
  • Serum IgM vs Decorin (BJ antigen): Testing
    • Decorin antigen
      • Proteoglycan
      • Located in muscle basal lamina
      • Myokine
    • Antigenic epitope: Chondroitin sulfate carbohydrate moiety
  • EMG: Myopathic ± Spontaneous activity
  • Muscle pathology
    • Variable muscle fiber size
    • Endomysial fibrosis
    • Large, irregularly shaped myonuclei
    • Endomysial deposition of IgM
    • Serum IgM binding to muscle endomysium
• Also see: Myopathy with deficient chondroitin sulfate C in skeletal muscle

ANTIBODIES IN CONNECTIVE TISSUE DISORDERS ¹

MYOSITIS-ASSOCIATED ANTIBODIES
Aminoacyl t-RNA synthetase Antibodies: IMPP syndromes
Autoantibody	tRNA-Synthetase Antigen	Antigen function	Clinical associations	HEp-2 IIF pattern
Jo-1	Histidyl	Protein synthesis   Intracytoplasmic Amino acid binding   to cognate tRNA	PM 15%-30%; DM-like 13% Lung fibrosis (ILD) Skin rash: Mechanics hands Raynauds Arthritis Fever Specificity > 95% HLA: DRw52; DRB1*0301	Cytoplasm: Speckled
PL-7	Threonyl		PM/DM 3%-5% of cases Antibody +: ILD > 90%     Milder than Jo-1	Cytoplasm: Speckled
PL-12	Alanyl		PM/DM 3% Antibody +: ILD > 90% Skin lesions	Cytoplasm Speckled (dense)
EJ	Glycyl		Antibody +: ILD > 90%;     DM 10% to 80%	Cytoplasm
OJ	Isoleucyl		PM/DM <3% Antibody +: ILD > 90% Skin lesions	Cytoplasm
KS	Asparaginyl 12		Antibody +: ILD > 90%     Myositis: 25% Skin lesions Japanese	Cytoplasm
Zo	Phenylalanyl		Myopathy + ILD	Cytoplasm
Ha (YRS)	Tyrosyl		Antisynthetase syndrome	Cytoplasm
Other Antibodies
Autoantibody	Antigen	Antigen function	Clinical associations	HEp-2 IIF pattern
SRP	Signal recognition particle   54 kD protein   In 7SL-RNA complex	Protein translocation   Intracytoplasmic   (Endoplasmic reticulum)	Immune polymyopathy   Specificity 93%   Acute onset; Severe HLA DRw52	Cytoplasm: Speckled Nucleolus
Mi-2	Helicase protein part of   NuRD complex	Nuclear transcription	DM 5% -35%; PM 5%-9% HLA DRw53 Rash: V- & Shawl-sign Cuticular overgrowth	Nucleoplasm Fine speckled
PMS1 6	PMS1	DNA mismatch   repair enzyme	Immune myopathy (7%) DM/PM/Fasciitis
TIF1γ/TIF1α p155/p140 14	Transcriptional intermediary   factors (TIF; TRIM33):   p155 = 1γ ; p140 = 1α	Nuclear transcription Cellular differentiation	Dermatomyositis (20%)   JDM (32%) Skin ulceration & edema Cancer-associated DM (75%)	Nucleus
MDA5	IFIH1 (CADM-140)	Immunity vs viral infection Detection of viral dsDNA	Dermatomyositis, Amyopathic ILD: Rapid progression Skin: Ulcers; Palmar papules	Cytoplasmic
NXP-2 15	Morc3	Nuclear transcription	Dermatomyositis,   Juvenile (23%); Calcinosis Adults: Lung Δ; Neoplasm	Cytoplasm
SAE	Small-ubiquitin-like   modifier enzyme (SUMO)	Post-translational modification   Nuclear transcription factors	Dermatomyositis, Adult (< 5%)   Amyopathic early
Decorin	Chondroitin sulfate	Extracellular matrix	Immune myopathy	Basal lamina
Ku	Thyroid autoantigen, 70-kD   G22P1	DNA protein kinase   regulatory subunit	Systemic sclerosis PM/Scleroderma Japanese	Nucleolus & Nucleus Homogeneous
KJ		? Translation factor	PM < 1%; Raynaud's Lung Fibrosis	Cytoplasm Speckled (dense)
HMGCR   (200/100)	3-Hydroxy-3-Methylglutaryl   -Coenzyme A Reductase	Cholesterol biosynthesis	Myopathy + Myalgias ? Statin use
Mup44	NT5C1A		IM-VAMP; sIBM Systemic sclerosis; SLE
Cortactin	CTTN		Immune myopathies
Nuclear pore	Nuclear pore proteins		Myopathy + Systemic	ANA: Peripheral
FHL1	FHL1		PM > DM > IBM

MYOSITIS-OVERLAP ANTIBODIES Associated with PM and other connective tissue disorders Sensitivity for connective tissue disorders up to 95% Antibody class: IgG
Autoantibody	Antigen	Clinical associations	HEp-2 IIF pattern
PM-Scl	Exosome: RNA processing complex PM/Scl-100 PM/Scl-75	PM 8%-12% Scleroderma 25% Caucasian	Nucleolus & Nucleus Homogeneous
56 kD	RNP component	PM/DM 87% Other CTD 10% High with active disease	?
SSA/Ro	2 proteins   & 4 small RNAs	PM/DM 5%-10% Sjögren's 90%	Nucleoplasm Fine speckled
U1-snRNP	3 proteins:   22, 33 & 70 kD	PM/DM 4%-17% SLE & Scleroderma 30% MCTD 95%	Nucleoplasm Speckled
U2-nRNP	Small nuclear RNP	PM/DM 4%-17% SLE & Scleroderma 30%	Nucleoplasm Speckled
U3-nRNP
Fer	Elongation factor 1a	PM/DM (rare)	?
MAS	tRNA bindingSer   protein	PM/DM (rare) HLA DRw53 Rhabdomyolysis Myalgias	Diffuse cytoplasm
Mitochondrial	PDC-E2	Histiocytic IM 1° Biliary cirrhosis Disease severity	Speckled
HSF1	HSF1	IIM + Neoplasm: 17% Other: RA, Sjögren 12%

Immune myopathies, Juvenile (JIIM): Antibody associations ²⁸

• TIF1γ/TIF1α (p155/140)
  • JIIM frequency: 23% to 30%
  • Clinical: Dermatomyositis syndrome
    • Muscle: Chronic course
    • Skin rash: Extensive; Photosensitive
    • Association: Lipodystrophy, generalized
  • Epidemiology: White patients
• NXP2
  • JIIM frequency: 12–23%
  • Clinical: Dermatomyositis syndrome
    • Muscle: Cramps & Atrophy, Dysphonia, More weakness
    • Joints: Contractures, weaker and have decreased physical function
    • Skin rash: Over joints; No truncal rash
    • Calcinosis
  • Epidemiology: White patients
• MDA5
  • JIIM frequency: Western 7%; Japan 33%
  • Clinical
    • Lungs: Interstitial disease
    • Muscle: Milder disease
    • Skin: Ulceration
    • Joints: Arthritis
• SRP
  • Epidemiology: More common in Japan & African-American females
  • Clinical
    • Muscle: Proximal weakness, severe; Chronic course; Serum CK high; Difficult to treat
    • Skin: Raynaud's; No rash
    • Cardiac
• Anti-synthetase: Similar syndrome to adults

CONNECTIVE TISSUE DISEASE: ANTIBODY TYPES (ANA is IIF pattern on HEp-2 cells)

• Anti-tRNA synthetase antibodies (IgG)
  

  General Antibodies   EJ   Jo-1   OJ   PL-7   PL-12   Other tRNA synthetases

  
  
  • Synthetase antibodies: General ⁵⁶
    • Geography: More frequent further from Equator ⁴⁸
    • Clinical: Multisystem syndromes
      • Myopathy
      • Pulmonary: Interstital lung disease
      • Skin: Rash
      • Joints: Arthritis
      • Neoplasms: No association
    • Muscle pathology features
      • Muscle fibers: Necrosis & Regeneration, preferentially near perimysium; Perifascicular or diffuse MHC Class I & II upregulation
      • Perimysial connective tissue: Histiocytes; Fragmented structure
      • IFN-γ-related gene upregulation
      • Tubuloreticular inclusions in some patients
    • Antibody associations
      • OJ
        • Clinical: Older patients; Disease duration shorter
        • Serum CK: Higher
        • Pathology: More muscle fiber pathology & inflammation (Histiocytes & Perivascular cells)
      • Jo-1
        • Clinical: Less fever
        • Pathology: More perifascicular location pathology & HLA-DR expression
      • PL-7: More multi-system clinical features
      • EJ: Muscle involvement; C_5b-9 on muscle fiber surfaces
  • Jo-1 ²¹
    • Antigen: Histidyl tRNA synthetase (HARS) (50-52 kD)
      • Location: Cytoplasm
      • Expressed in: Regenerating, not adult, muscle fibers
      • Function: tRNA synthetase
      • Hereditary disorders
        • Sensory-predominant neuropathy, Dominant
        • Usher syndrome type 3B , Recessive
    • Epidemiology: Most common synthetase autoantibody
    • Clinical syndrome
      • Myopathy: Immune
        • Weakness (80%): Proximal > Distal; Respiratory (13%)
        • Myalgias (80%)
        • Pathology: Perimysial connective tissue damage (IMPP)
        • Treatment: May be refractory to corticosteroids
      • Interstitial Lung Disease: Especially
        • Nonspecific interstitial pneumonia (NSIP) pattern
        • Lower lung fields
      • Raynaud's
      • Skin disorders (30%)
      • Arthritis
      • Onset: Spring
      • Neoplasm association
        • Frequency: 12%
        • Age: > 50 years old
        • Type: GI; Gynecologic
      • Therapy
        • Myopathy: Often initially improves with corticosteroids
        • Lung disease: Less responsive
          
        • Prominent flares when tapering drugs
        • May require other immunmodulating medications: Methotrexate; Rituximab
    • Laboratory
      • Serum: Synthetase antibody
      • ANA: Cytoplasmic (speckled)
      • Immunology
        • HLA associations
          • HLA-DR3/-DRw52
          • HLA-B*08:01 & position 9 aspartic acid
          • HLA-DRB1*03:01 & position 74 arginine & leucine
        • Antibody isotype: IgG1
      • Associated Ro52 (TRIM21) antibody: Some patients
      • Muscle pathology: Immune myopathy with perimysial pathology (IMPP)
    
    
  • PL-7 ²¹
    • Antigen: Threonyl tRNA synthetase (TARS)
    • Hereditary disorder
      • Trichothiodystrophy 7, nonphotosensitive (TTTD7) (Brittle hair)
    • Epidemiology
      • Females 60%
      • Higher frequency with more UV exposure ⁴⁸
    • Clinical
      • Onset age: Median 60 years
      • Interstitial lung disease (90%)
        • Dyspnea
        • Cough
        • May be asymptomatic
        • Course: Usually progressive; May precede myopathy
        • Poor prognosis: DLCO < 45%; UIP pattern on HRCT
        • Poor response to treatment: 30%
      • Immune myopathy (90%): Improved with treatment
      • Skin
        • Raynaud's phenomenon (40%)
        • Mechanic's hands (30%)
      • Joint impairment (40%)
      • Pericardial effusion (20%)
      • Esophageal/gastrointestinal involvement (20%)
      • Neoplasm (3%)
      • Course
        • Relapse: 30%; Prednisone <20 mg/day
        • Mortality: 15%
      • Treatments
        • Prednisone: 0.5–1 mg/kg per day
        • Immunomodulation
    • Laboratory
      • HRCT patterns: NSIP; UIP; Some COP
      • Serum CK: Less often very high (> 3,000) vs. Jo-1 Ab patients
      • Serum: Synthetase antibody
    
    
  • PL-12
    • Antigen: Alanyl tRNA synthetase (AARS)
    • Epidemiology
      • Common in Southwest US
      • Females 80%
      • Frequency: < 5% of anti-tRNA synthetase antibodies
    • Clinical
      • Onset age: Median 51years; 39 to 73 years
      • Interstitial Lung Disease predominant (90%)
        • NSIP or UIP
        • Pulmonary hypertension (40%)
      • Raynaud's (65%)
      • Immune myopathy
        • Frequency: 50%; Sub-clinical 20%
        • Pathology: IMPP
      • Fever
    • Laboratory
      • ANA +: 50%
      • Serum: Synthetase antibody
    • PL-12 hereditary disorder: CMT 2N
    
    
  • EJ ²²
    • Antigen
      • Glycyl tRNA synthetase (GARS) (75 kD)
      • GARS hereditary disorders
        • Charcot-Marie-Tooth disease, type 2D (CMT 2D)
        • Neuropathy, distal hereditary motor, type V (HMN 5A; SMAD1)
    • Epidemiology
      • Females (50%)
      • Infrequent anti-tRNA synthetase antibody
    • Clinical
      • Lung (70%): Interstitial Disease
        • Dyspnea
        • NSIP or atypical UIP
        • Lymphoid follicles
      • Skin (30%): Finger tip lesions; Rash on neck & shoulders
      • Associated immune disorders
        • Undifferentiated connective tissue disease (50%)
        • Rheumatoid arthritis
      • Myopathy: Occasional patient
        • Weakness: Proximal
        • Myalgias
    • Laboratory
      • ANA+: 70%
      • Serum CK
        • Usual: Normal or Occasionally high
        • Rarely: > 3000
      • Serum: Synthetase antibody
      • Serum Aldolase: Normal or Mildly high
      • Muscle pathology
    
    
  • Other target Synthetase antigens: Associated with similar clinical syndrome & cytoplasmic ANA
    • OJ = isoleucyl (IARS) : ILD predominant
    • KS = asparaginyl (NARS) : ILD predominant
    • Zo = phenylalanyl (FARSA) : Myopathy + ILD
    • Ha = tyrosyl (YARS)
    • Lysyl (KARS)
  • Other tRNA synthetase disorders: Hereditary
    • Cytoplasmic ARS
    • Mitochondrial ARS
  
  
• Anti-KJ
  • ANA: Cytoplasm (dense speckled)
  • Antigen: Unidentified factor in protein translation
  • Clinical: Similar to anti-synthetase antibodies
  
  
• Anti-Signal Recognition Particle
  • ANA: Cytoplasm (speckled) and nucleolus
  • Antigen Targets
    • 54 kD protein
    • 72kD protein subunit
    • 7S RNA
  
  
• Anti-Ribosomal RNP
  • Antigens: Phosphoproteins in elongation step of protein synthesis
  • ANA: Cytoplasmic (dense); Nucleolar (homogeneous)
  • Clinical
    • Clinical associations: SLE
      • Prevalence: 10% to 20%
        
      • Cerebritis with psychosis: 56% to 90%
• 56 kD RNP component
  • ANA: ?
  • Clinical associations
    • Polymyositis/Dermatomyositis: 87%
    • Other connective tissue diseases: 10%
    • Titers related to disease activity
  
  
• Giantin ¹⁰
  • Location: Golgi
  • Molecular weight: 372 kD
  • Disease associations
    • Myopathy with reduced α-dystroglycan
    • Connective tissue disorders: Sjögren; Scleroderma; Rheumatoid arthritis
    • HIV positive: Low titer
  
  

  NXP-2 (p140; MJ) 15 p140 antigen Identity: NXP-2 protein (MORC3) Location: Nucleus, except nucleolus Binds dsDNA Forms MORC3 nuclear bodies: ATP dependent Possible functions RNA metabolism Maintenance of nuclear architecture Modulates IFN responses to viruses Clinical associations Clinical Epidemiology Onset age distribution: Bimodal, Means 8 & 52 years More frequent in more Northern locations 48 Association with immune myopathy: 75% Frequency in immune myopathies Adults: 5%; More in younger adults vs other autoantibodies Children: 10% to 20% Immune myopathies: Clinical syndromes Dermatomyopathies (75%) Juvenile DM (DM-VP) Adult DM (DM-VP) Regional Ischemic Immune Myopathy (RIIM) Myopathy without Skin rash NXP2 variant: Juvenile DM (20%) Muscle Weakness: May be more severe at onset Cramps (39%) Atrophy Skin Rash: Heliotrope; Gottron papules Periungual erythema Subcutaneous edema Dysphonia Mild disease (76%) Systemic Calcinosis (37%) Worse in younger children (< 4 years) GI Perforation 42; Ulceration & Bleeding Dysphagia Joint contractures Disease course High frequency of hospitalization Monocyclic Treatment resistant 41 Frequency: Up to 40% Associations Clinical Edema Skin ulcers Weakness, Severe Dysphagia Laboratory Lymphocytes: CD4:CD8 < 1.4 Ferretin > 200 μg/ml BMI low ANA+ NXP2 variant: Dermatomyopathy, Adult 29 Frequency: 23% Muscle Weakness More severe Distal & Proximal Dysphagia Atrophy: More prominent Myalgias: More frequent Skin Subcutaneous edema (2x more frequent) Limbs & Face Muscle association: Necrosis in some; No inflammation Periungual changes Photosensitivity Hyperpigmentation Heliotrope rash Gottron papules Calcinosis (30%) More frequent No association with muscle disease severity Lung disease (9%) Interstitial Less frequent than IMPP Neoplasms Frequency: 3.7-fold increased Types: Lymphoid (CLL;, Waldenström), Ovary,   Prostate, Pancreas, Gall bladder, Lung May also have: Anti-synthetase or PM/Scl antibodies Treatments: Often resistant Corticosteroids Tofacitinib Methotrexate IVIg Myopathy without Skin rash 15 Frequency: 35% of NXP2 antibodies Clinical Onset age: Adults Muscle Weakness: Proximal ± Distal (47%) Myalgia Skin: Subcutaneous Calcinosis Edema Laboratory Serum CK: Normal or High Muscle pathology: RIIM with more severe weakness Laboratory Serum CK: Normal to 8,000 ANA+: 40% HLA association: DRB1*08 Muscle 33 General patterns: Several different; All with vessel pathology Dermatomyositis with Vascular Pathology (DM-VP) Regional Ischemic Immune Myopathy (RIIM) Minimal Myopathy with Capillary Pathology (MMCP) Perimysial vessel walls Thick Lipid accumulation Endomysial capillaries 43 Numbers: Reduced regionally or diffusely C5b-9 deposits Endothelium: Lost Muscle fibers: Varied pathology Necrosis, clustered Perifascicular myopathy Edema: Regional

  Skin Rash: NXP-2 Dermatomyopathy From: Renatta Knox Nails & Skin: NXP-2 Dermatomyopathy, Teenager From: Renatta Knox

  MDA5 (CADM-140; IFIH1) antibody 19 Antigen Adults   Cutaneous   Pulmonary   Lymphopenia   Other Children Laboratory Antigen: MDA5 protein Properties RNA-specific helicase Retinoic acid-inducible gene (RIG)-like receptor Functions: Recognizes single-stranded RNA viruses Interferon inducible Location: Cytoplasm Mutations Induction of type I interferon activity Inheritance: Dominant Aicardi-Goutières syndrome 7 (AGS7) Clinical Psychomotor development: Delayed; Lack of speech Tetraparesis: Spastic-Dystonic Hypotonia: Axial Spastic paraparesis IFIH1 mutation: Missense; Gly495Arg Child onset Spasticity Multisystem inflammation MDA5 antibody in Adults: Clinical associations Epidemiology Geography Most commonly reported in Japan & China Japan: Rural > Urban; Rural onset in Fall US: 10% of Dermatomyositis, especially "amyopathic" Dermatomyopathies Asian 11% to 60% Caucasian 7% to 16% Age: Children & Adults Female (60% to 80%) Seasonal: More common October thru December 57 Skin (74%) Palmar papules Tender & Painful Location: Metacarpophalangeal & Interphalangeal joints Central coloration: Ivory Ulcers (80%) Locations Oral Hands: Lateral nailfolds, Gottron papules Over joints: Elbows, Knees Pathology: Vasculopathy Fibrin deposition Perivascular inflammation Endothelial cell injury Mechanic hands V-rash Raynaud's Calcinosis Hand swelling Intersitial lung disease (ILD) (78%) 35 Common: Rapidly progressive ILD Types Acute/Subacute Interstitial Pneumonia (AIP) Common More frequent than in anti-synthetase syndromes Pneumonia Patterns Organizing (OP) (21%) Nonspecific Interstitial (NSIP) (60%) Pneumocystis jirovecii 50 High prevalence & mortality More with: Immunosuppression Often: Early in disease course Worse prognosis Increased age Serum LDH high Common (60%) Also occurs in: Anti-synthetase syndromes Usual Interstitial Pneumonia (UIP) (13%) Fibrosis: Common Clinical correlations Increased mortality (8x): Most in 1st year of disease Dermatomyositis cohorts: ILD less severe Course 30 Rapid progression: 33% to 60% May respond to immunosuppressive treatment vs ARS antibody-associated ILD Disease severity: More Treatment response: Less Prognosis: Worse; 5 year mortality 50% Muscle Most patients: Mild or Minimal disease Weakness: 58% Pain: 47% Muscle biopsy: May have mild, or no, muscle fiber pathology GI Oral: Pain and/or Ulceration Dysphagia Bone Osteonecrosis of femoral head: 3.5x increased risk 58 Joint: Arthritis/Arthralgia: 42% to 80% Symmetric polyarthropathy May be presenting feature Location: Small hand joints Non-erosive Similar to: Rheumaroid or Psoriatic arthritis Hair loss (Alopecia): Diffuse (80%) Fever (63%) Infection susceptibility Cytomegalovirus 44 Increased frequency Shorter survival CD4 T-cells & CD20 B-cells: Reduced Malignancy: Rare Course Persistent high titers: Increased mortality Dermatomyopathy + 32 MDA5+ ILD: More frequent Survival: Reduced Poorer prognosis IgG1 MDA5 antibodies Serum ferritin level > 1000 ng/ml Increased neutrophil–lymphocyte ratio Ground-glass opacities in all six lung fields Worsening of pulmonary infiltrates during therapy Pneumocystis jirovecii pneumonia 50 MDA5+ & SSA/Ro52 positive More common in non-survivors (44%) Lower survival (50%) over 1st 2 years MDA5+ & ≥ 60 years of age Skin & Joint involvement: Less Immunosuppressive treatment: Less response Mortality: Higher Clinical remission: Titers reduced or absent Treatment Corticosteroids: Often poor response Other + Steroids: Cyclosporine, Tacrolimus, Cyclophosphamide Tofacitinib (Janus kinase (JAK) inhibitor) Dose: 10 mg/day Viral side effects commmon Pirfenidone (Anti-fibrotic agent) MDA5 antibody in Children: Clinical associations 38 Epidemiology Frequency in Juvenile IIM: 8% in North America; Higher in Asia UV irradiation Residential No season association Onset age: Older than other Juvenile IIM Common Weight loss (80%) Fever Skin Gotron's papules Photosensitivity Periungual capillary changes Ulcerations Alopecia Adenopathy Joints: Arthritis & Arthralgias Interstitial lung disease (ILD) Dyspnea Less frequent than anti-synthetase Ab IIM Serum CK & Aldolase: Low Uncommon Severe weakness Falling Dysphagia Chronic course (29%) Laboratory MDA5 antibodies IgG IgG1 ± IgG3 subclass with DM-ILD 45 More severe & rapidly progressive disease Survival: Lower More immunogenic amino acid regions (50%): 226-315, 541-630, 856-945 Course: No change over time or with treatment Low titers: Often less severe disease Associated antibodies ANA: 40% to 65% ENA: 40% to 65% SSA/Ro52 antibodies (30%): Associations Rapidly progressive Interstitial lung disease Mortality: Higher risk SFPQ : Reduced risk of arthritis Frequency: High in 27% Prognosis: Worse Anti-viral 57 Increased: Capsid protein 1 (VP1) of enterovirus B Decreased: Rhinovirus A Serum markers Serum CK: Often normal; High in 30% High Aldolase with Normal CK: 60% GGT & ALT: High Ferritin Levels High (≥ 1600 ng/ml) Correlate with: IL-6, IL-10, IL-18 Clinical correlations of high ferritin Poor prognosis Poor response to treatment T-cells: Lymphopenia 49 Patterns CD4+: Reduced CD8+: Reduced CD4+/CD8+: Increased More common than in other IIM Clinical correlations: Severe lymphopenia (< 550 cells/μL) Interstitial lung disease: More rapidly progressive Skin: Ulcers more common Chest CT imaging patterns Lower consolidation or ground-glass attenuation (GGA) (50%) Random GGA (33%) Lower reticulation: Uncommon No intralobular reticular opacities EMG: Myopathic 75%; Irritable 40% Myopathy

  MDA-5 Palmar Papules Nailfold Ulcers From: D Fiorentino

  
  
• SAE (SUMO) antibody ^{20, 138}
  • SAE Antigen
    • SUMO protein
    • Immunoprecipitation: 40 kD & 90 kD bands
  • Clinical features: Dermatomyositis (7%)
    • Onset age: Adult; Rare child
    • Skin: May be severe
      • Rash, violaceus: Shawl sign; Angel wings
      • Gottron's papules
      • Photosensitive
      • Panniculitis
      • Course: At disease onset
    • Myopathy (60%)
      • Weakness: Proximal; Mild
      • Dysphagia: 39% to 80%
      • Course: Develops after Skin rash
      • Some patients: Hypo- or Amyopathic
    • Interstitial lung disease: Varied; Common in some populations
    • Systemic features unusual: Fever; Weight loss
    • Neoplasm
      • General: Rare; Ovarian in 1 patient
      • China & Asia: Increased frequency ⁴⁶
  • Laboratory
    • Serum CK: Normal to Mildly high
    • Associated antibodies
      • Mi-2 (40%): Weak positive
      • Ro52
  
  
• Cortactin antibody ³⁹
  • Cortactin (CTTN) protein ²⁴
    • Interacts with Kv1.2
    • Associated with: Membrane ruffles & lamellipodia; Dendrites
    • Neuromuscular junction
      • Post-synaptic
      • Promotes AChR clustering: Downstream from Agrin/LRP4/MuSK
  • Clinical associations
    • Immune & Inflammatory myopathies ²⁴
      • Clinical syndromes
        • Active myopathy, Immune: 26%
        • Polymyositis: 20%
        • Dermatomyositis: 8% to 15%
        • Inclusion body myositis: 0%
        • Juvenile myositis 2%
        • Healthy controls 4%
      • Clinical features
        • Interstitial lung disease: Higher titers
        • GI: Dysphagia; Reflux
        • Skin: Mechanic's hands
        • More hospitalizations
        • Serum CK: Lower
      • Antibody associations: Ro-52; NT5C1a; Mi-2; NXP2
    • Myasthenia gravis: "Sero-negative" ²⁴
      • Frequency in AChR & MuSK Ab- MG: 20% to 25%
      • Onset age: 35 years
      • Female: 78%
      • Weakness
        • Restricted ocular: 67%
        • Generalized, mild: 33%
        • No bulbar onset
      • Thymoma: 0%
    • Other disorders
      • AChR Ab-positive MG: 5% to 10%
      • Healthy controls: 5%
      • Other autoimmune disorders: 3% to 13%
      • Other myopathies: 4%
  
  
• FHL1 antibodies ²⁷
  • FHL1 protein
  • Antibody type: IgG
  • Clinical associations: Idiopathic inflammatory myopathies (IIM)
    • Frequency
      • IIM: 25%
        • Polymyositis: 58%
        • Dermatomyositis, Adult: 30%
        • Dermatomyositis, juvenile: 3%
        • Inclusion body myositis: 9%
      • Other immune disorders: 1% to 6%
      • Healthy control: 2%
      • Non-inflammatory NMD: 0%
    • Cliinical in IIM
      • Muscle atrophy
      • Dysphagia (85% vs 54%)
      • Weakness: More distal (94% vs 74%)
      • Outcome: Worse
    • Relation of antibodies & titers to
      • Disease phase: Present early in course
      • Treatment outcome: Varied reports; May fall with immunosuppression
      • Clinical disease activity: More
      • Strength measures: Worse
      • Serum CK levels: Higher
      • Ro52 & PM/Scl antibodies: May be more frequent
      • Muscle pathology: MHC1 upregulation more frequent
    • HLA DRB1*03/*13 genotype: More frequent
  • Myopathologic associations
    • Muscle fiber damage: More necrosis (26% vs 9%)
    • Endomysial connective tissue: Increased (44% vs 14%)
    • Vasculitis (18% vs 3%)
    • FHL1 with focal accumulation in muscle fibers

• anti-Centromere antibodies ¹³
  • ANA: Diffuse speckled nuclear (Centromere)
  • HLA type association: Non-leucine residue at position 26 of HLA-DQB1 chain
  • Protein target: Antigens localized at the kinetochore plates
    • Primary Scleroderma: Centromere protein-B (CENP-B)
    • Other proteins: CENP-A ; CENP-C
  • Clinical
    • Systemic scleroderma, Primary
      • Sensitivity: 5% to 33%
      • Specificity: High (99%)
      • Higher frequency of multisystem involvement
        • Raynaud’s phenomenon
        • Xerophthalmia
        • Peripheral neuropathy (25% vs 2%)
        • Primary biliary cirrhosis
      • Less frequent: Anti-SSA or SSB antibodies
    • Scleroderma variants
      • CREST (60% to 80%)
      • Raynaud's: Primary
    • Other associations
      • Raynaud’s disease with primary biliary cirrhosis (30%)
      • Systemic lupus erythematosus (4%)
      • Mixed connective tissue disease (8%)
      • Rheumatoid arthritis (1% to 7%)
• anti-dsDNA (Double-stranded DNA) antibodies
  • ANA: Homogeneous nuclear pattern
  • Clinical
    • Active SLE (40% to 70%)
    • Nephropathy: High avidity antibody
    • CNS: Low avidity antibody
    • Marker of disease activity
  • In vivo target: Nucleosome
• Anti-Mi-2 (NuRD) antibody ³⁴
  • Epidemiology
    • HLA type associations
      • DRw53; DR7 in most
      • Tryptophan at position 9 of DRβ chain
      • HLA-DRB1*07:01
    • More in
      • Hispanic patients
      • Locations near Equator ⁴⁸
  • Target Antigens: Mi-2α (CHD3) & Mi-2β (CHD4)
    • SNF2-superfamily helicase: Contains zinc fingers & helicase motifs
    • Size: 220 to 260 kD
    • Cell location: Nucleus
    • Cross reactivity ⁵⁹
      • AIRE
      • SP140L
      • Tif1γ
    • Functions
      • Component of nucleosome (chromatin) remodeling & histone deacetylase machinery (NuRD)
      • DNA-binding: Transcriptional regulation at chromosomal level
      • Barrier to transcriptional activation: Opposition to other chromatin remodelers (SWI/SNF)
      • Regulates developmental processes
      • Skin
        • Development & repair of basal epidermis
        • Upregulated in keratinocytes after UV irradiation
      • Muscle
        • Upregulated in: Immature or regenerating muscle fibers ¹⁷
        • Downregulation: Accelerates differentiation of myoblasts in vitro
    • ANA: Speckled nuclear pattern
  • Clinical associations
    • General
      • Dermatomyositis
      • Few other associated connective tissue disorders
    • Epidemiology
      • Children: Hispanic ethnicity
      • Common in India
    • Onset
      • Acute
      • Adult or Child
    • Skin
      • Nailfold involvement: Periungual edema
      • Face: Malar rash; Dermatitis
      • Ulceration
      • Shawl sign
      • Lipodystrophy
    • Muscle (Weakness)
      • Common: 60% at onset; 98% during course
      • Pattern: Proximal
      • Bulbar (20%)
      • Course: Occurs within 1st 2 years of disease
    • Myalgia (25%)
    • Calcinosis: Uncommon
    • Other systemic
      • Malignancy: No association
      • Interstitial lung disease: Varied; Up to 40%
    • Disease course
      • Severity: Mild (63%)
      • Chronic
      • Treatment response: Common
      • Survival
        • Low mortality
        • Better than MDA-5 antibody-associated disease
  • Laboratory
    • ANA + (100%): Fine speckled
    • Serum CK: Higher than Mi-2-; Mean 3,000
    • Muscle MRI: Atrophy; Fat replacement; Edema
    • Antibodies
      • Mi-2 course: Titers may decline or normalize with remission
      • Ro52: Less frequent (17%) than with Antisynthetase antibodies (81%)
      • SAE antibodies: Some association with Mi-2
    • HLA alleles: MxA+ muscle fibers present ⁵²
      • DRB1*04:07
      • DQB1*06:01
    • Skin: Pigment incontinence
    • Muscle pathology ⁵¹
      • Muscle fibers
        • Necrosis
          • Central necrotic/Peripheral regenerating fibers
          • Frequency: More than Mi-2-
          • Distribution: Scattered muscle fibers
        • Perifascicular pathology
          • Muscle fiber atrophy or necrosis (59%)
          • MHC1 upregulation: More prominent
          • Cytochrome oxidase: Reduced in muscle fibers in some patients
          • MxA+ muscle fibers
        • MxA+ fibers present: Some small fibers
      • C_5b-9 stain: Endomysial connective tissue
      • Perimysial connective tissue damage
        • Common
        • Fragmentation
        • Perimysial histiocytes
        • Alkaline phosphatase stain +
      • Inflammation (48%): Associated with smaller vessels
      • Endomysial capillaries
        • Number: Mildly reduced or Normal
        • Alkaline phosphatase+
        • C_5b-9 deposition: Unusual
      • Gene expression: MADCAM1 increased
• anti-Ro/SSA
  • hY RNP peptide (60 kD) antigen
    • Associated with hY RNA (short & uridine rich) in ribonucleoproteins
    • Location
      • Mostly in cytoplasmic compartment (70%)
      • Few in nuclear compartment (30%)
      • Cytoplasmic membrane or in small blebs during apoptosis
    • ? Involved in ribosomal RNA discard pathway
      • Binds misfolded 5S rRNA precursors
      • May function in quality-control pathway for ribosome biogenesis
    • ? Protect against autoantibody development
      • Mechanism: Sequester defective ribonucleoproteins from immune surveillance
    • Knockout mice: Develop autoimmune syndrome
      • Antibodies: Anti-ribosome; Antichromatin
      • Glomerulonephritis
      • Some strains: Sensitivity to irradiation with UV light
  • 52 kD antigen (Ro-52; TRIM21) ¹⁸
    • SSA (ENA) antibodies most commonly bind to this polypeptide
    • Clinical associations
      • General
        • Not diagnostically specific
        • May become positive after IVIg treatment
      • Congenital complete atrioventricular block (CAVB)
        • Maternal 52-kD Ro and 48-kD La antibodies
        • HLA region SNP associations: Near MICB gene; C6orf10
      • Autoimmune liver disease: Primary biliary cirrhosis; More severe course
      • Celiac disease
      • Myositis (30%)
        • Clinical Sjögren’s syndrome: Uncommon
        • Ro-52 antibody + Anti-Synthetase antibody
          • Myositis: Severe
          • Joint involvement
          • More: ILD; Skin rash
          • Anti-Jo-1 antibody: 40% to 72%; Worse prognosis
        • Ro-52 antibody without Jo-1 antibody
          • Dermatomyositis
            • No Mechanic's hands (60%)
            • Lung disease less common
          • Females (90%)
        • Association with: NT5C1a antibody
      • Solid tumor relapse
      • SSc (20%)
      • Ro52 vs Ro60 antibodies ⁵⁴
        • Ro52 without Ro60: More
          • Myositis
          • Non-rheumatic diseases
          • Arthritis
          • Interstitial lung disease
          • Older age
          • Males
        • Ro60 ± Ro52: More
          • Systemic lupus erythematosus
    • Other features
      • Antigenic molecule may be poly-ubiquitinated
      • Action: Interrupts atrioventricular conduction & L-calcium channel influx of fetal cardiocytes
      • TRIM21 protein expressed on brain microvasculature
  • Other components of Ro/SSA
    • 54 kD peptide
  • ANA: Fine speckled
  • Clinical
    • Sjögren's syndrome, Primary (50% to 60%): Increased frequency of
      • Earlier disease onset
      • Longer disease duration
      • Salivary gland: Enlargement; Severity of lymphocytic infiltration of minor salivary glands
      • Extraglandular manifestations: Lymphadenopathy; Purpura; Vasculitis
    • Scleroderma (Systemic sclerosis)
    • Lupus (35% to 50%): Specific syndromes
      • Cutaneous (70%)
      • Neonatal (born of SSA mothers) associations
        • Congenital complete heart block
        • QT interval prolongation
      • Old onset (> 90%)
      • C2 & C4 deficiencies
      • ANA-negative
      • Asian (50% to 60%)
      • Lupus nephritis: Neuropathy
    • Immune & Inflammatory myopathies
      • Common in Koreans (24%)
      • Jo-1 antibodies
      • MDA5 antibodies
      • IBM (IM-VAMP): Females
• anti-La/SSB
  • 48 kD antigen: Termination factor for RNA polymerase III
  • ANA: Fine speckled
  • HLA association: Leucine at position 26 of HLA-DQB1 chain
  • Clinical
    • Lupus; Especially neonatal
    • Sjögren's syndrome
• anti-SS-56
  • Structurally related to 52-kDa Ro/SSA antigen
  • Localization: Perinuclear cytoplasmic
  • Associated with: Visceral complications in SLE
  
  
• anti-Histones
  • ANA: Homogeneous nuclear pattern
  • Clinical
    • Drug induced SLE (95%)
    • Systemic sclerosis with lung fibrosis
• anti-Nucleosomes ³
  • Definition: Fundamental unit of chromatin
  • Composition
    • Octamer of 2 copies each of Histones H2A, H2B, H3 & H4
    • 146 base pair helical DNA wraps structure
  • Generated during apoptosis
  • Nucleosomes are immunogen for & in vivo target of lupus anti-dsDNA & anti-histone antibodies
  • Disease sensitivity & specificity of anti-nucleosome antibodies
    • IgG: SLE (72%); Scleroderma (46%); Mixed connective tissue disease (45%)
    • IgM: SLE (66%); Scleroderma (22%); Mixed connective tissue disease (45%); Antiphospholipid syndrome (25%)
    • Overall presence in SLE
      • Frequency: 80% to 90%
      • Disease activity: Present in active & inactive disease; Titers correlate with activity
      • IgG3 anti-nucleosome antibodies may play role in pathogenesis of lupus
• anti-Sm antibodies
• anti-U1-nRNP : 70 kDa polypeptide
• anti-U2-nRNP
  • ANA: Speckled ribonuclear pattern
  • Clinical association: Scleroderma
• anti-U3-RNP ¹⁶
  • Antigen
    • U3 small nucleolar RNA
    • Subunits: 6 or more
      • Fibrillarin: 34 kDa; Main antigen
  • Clinical association: Scleroderma (Systemic sclerosis (SS))
    • More common with
      • African American race
      • Male sex
    • SS higher frequency of
      • Skeletal muscle involvement
      • Pulmonary arterial hypertension
    • Myopathy
      • Weakness: Proximal; Dysphagia
      • Serum CK & Aldolase: High
      • MRI: Signal in thigh extensors & flexors
      • Muscle: CD8 cells; MHCI expression by muscle fibers
• anti-Topoisomerase (Scl-70)
  • Topoisomerase: Nicking closing activity on DNA
  • Disease associations
    • Systemic sclerosis
      • Myopathy with Capillary Pathology
    • SLE (26%): Correlates with Disease activity, Pulmonary hypertension, Nephritis
• TIF1γ/TIF1α (p155/p140) antibodies ¹⁴

  Epidemiology Antigens Adults Children Subtypes DM: DDx

  • Epidemiology
    • HLA associations
      • DQA1*0301 in Caucasian patients
      • DQB1*02: Subgroups
        • HLA-DQB1*02:01: Juvenile onset disease
        • HLA-DQB1*02:02: Adult onset disease
    • Dermatomyopathy onset: Children & Adults
  • Antigens: Transcriptional intermediary factors
    • p155 = TIF1γ (TRIM33)
    • p140 = TIF1α (TRIM24)
    • Some patients also have serum IgG binding to: TIF1β (100 kD; TRIM28)
    • Most common: Binding to both TIF1γ & TIF1α
      • Malignancy & Truncal erythema
        • Binding to both (73% & 77%) > TIF1γ alone (50% & 33%)
    • Location: Nuclear
  • TIF1γ Clinical syndrome: Dermatomyositis with Cancer Risk in adults

    Epidemiology: Male = Female Clinical Onset age: Often > 60 years Dermatomyositis syndrome Skin V-sign rash & Shawl sign Face: Dermatosis with longer disease course Rash at hairline Nailbeds: Capillary pathology Photosensitive Palmar hyperkeratosis Psoriatic-like plaques (Red on White) Weakness (77%) Legs & Arms Proximal Interstitial lung disease: Occasional; Mild Mouth: Erythematous patch on posterior hard palate (Ovoid palatal) Neoplasm associations Frequency: 50% to 78% Increased associations of Tif1-γ dermatomyopathy with neoplasm Age: Older Sex: Male Dysphagia Skin: V-neck rash Tif1γ antibody isotype: IgG2 Cancer associations Frequency: 27x > Antibody negative Dermatomyositis Organs: Gastric, Lung, Breast, Esophageal, Bladder,   Colorectum, Ovary, Thymus Neoplasm: Histopathology types Common: Adenocarcinoma Also: Squamous cell, Transitional cell,   Small cell lung, Lymphoma Laboratory Serum CK: Normal to Very high Antibody associations Sp4 47 > 90% also TIF1γ + Reduced risk of associated neoplasm in TIF1γ + patients Disease frequency Dermatomyositis 12% Rheumatoid arthritis 3% Controls 3% CCAR1 Reduced risk of associated neoplasm in TIF1γ + patients Effects of treatment: TIF1γ antibody titers reduced Muscle pathology Anatomic distribution: Regional Varied: Near vascular bundles; Clustered; Perifascicular Atrophy: Perifascicular predominant Muscle fiber pathology Distribution: Perifascicular or Clustered Muscle fiber pathology types Vacuoles Aggregates: LC3; AMPDA Internal architecture: Irregular; Dark stained COX: Reduced stain intensity MHC Class I: Upregulated, Perifascicular MxA: Cytoplasm staining, Perifascicular Necrosis 20% of patients Distribution Clustered or Perifasciular RIIM pattern Vessels Capillaries (Endomysial) C5b-9 deposits: In regions of muscle fiber pathology Ulex stain: Reduced capillary numbers Esterase stain: Increased on many capillaries Alkaline phosphatase stain: Increased numbers with + stain Perimysial vessels: Perivascular lymphocytes in some patients Perimysial connective tissue (near vessels): Histiocytes; Some patients Skin pathology Poikiloderma Flagellate erythema Bullae

    Nail & Nailbed pathology

  • TIF1γ Clinical syndrome: Juvenile Dermatomyositis
    • Epidemiology: Higher UV exposure in white males
    • Clinical
      • Dermatomyositis syndrome
        • General: More severe, or diffuse, skin involvement
        • Gottron papules
        • Rash: Malar rash, "Shawl-sign
        • Photosensitivity
        • Cuticular overgrowth
        • Capillary changes: Periungual; Nailfold
      • Weakness: Proximal; Arms & Legs
      • Systemic
        • Calcinosis (30%)
        • Lipodystrophy
          • Focal or Generalized
          • May have similar frequency in JDM with or without antibody
      • Disease course: Chronic illness
    • Laboratory
      • Creatine kinase (CK) levels: Lowest
      • TIF1γ antibody isotype: IgG₄
  • Tif1γ antibody: Immune syndrome associations
    • Juvenile dermatomyositis with no neoplasm (29% to 36%)
    • Juvenile CTD-associated myositis (33%)
    • Adult dermatomyositis (21%): Often younger adults (25 to 39 years) & Amyopathic
    • Adult CTD-associated myositis (15%)
    • Cancer-associated dermatomyositis: Older adults (Usually > 45 years) (73% to 75%)
    • Dermatitis, Clinically Amyopathic ⁵³
• TRIM72 (MG53) antibodies ³⁷
  • Epidemiology: 11% of Immune myopathies
  • Antibody
    • Type: IgG
    • Effect: Impair sarcolemmal repair
    • Commonly occur in patients with other IIM-related antibodies
    • Other TRIM antibodies: Tif-1; Ro-52
  • Clinical
    • Present in: Immune myopathies ± Skin pathology
  • Trim72^-/- mice: Myopathy
• Nuclear Pore (Nup) complex (NPC) antibodies ²⁶
  • Epidemiology: 4 French-Canadian patients
  • Antibody
    • Type: IgG; Some IgA or IgM
    • ANA pattern: Punctate peripheral nucleus staining
    • Antigens: Nup358/RanBP2, Nup90, Nup62, gp210
    • Titers associated with myositis activity
  • Clinical: Immune myopathy + Systemic
    • Myositis
      • Weakness: Proximal; Symmetric; Moderately severe
      • EMG: Myopathy, Irritable
      • Muscle: Inflammatory myopathy
      • Serum CK: 1765 to 4836
    • Arthritis: Erosive
    • Trigeminal neuralgia,
    • Interstitial lung disease (50%): Mild
    • Raynaud phenomenon
    • Weight loss.
    • Course: Chronic; Relapsing; 100% long term survival
    • Treatment: Requires corticosteroids + 2nd drug (Methotrexate or Azathioprine)
    • No cancer, skin or liver disease
  • Laboratory
    • MHC class II allele DQA1*0501
    • Anti-CCP & rheumatoid factors
  • Other disorders
    • Primary biliary cirrhosis: gp210 & p62
• Heat Shock Factor 1 (HSF1) ³⁶
  • Nosology: Heat shock transcription factor
  • Target antigen: HSF1
    • Locations: Nuclei (Especially in stressed cells) & Cytoplasm
    • Muscle fibers, Immature: Increased expression
  • Antibody
    • Type: IgG
  • Clinical associations
    • Immune & Inflammatory Myopathies
      • Frequency: 11%
      • Dermatomyopathies
      • Muscle weakness (66%)
      • IIM + Neoplasm: 17.5%
      • IIM without Neoplasm: 7.5%
      • Higher levels: More disease activity
      • Other myositis antibodies: MDA5 (27%); Tif1γ (20%)
    • Rheumatoid arthritis: 11%
    • Sjögren’s syndrome: 12%
    • Systemic lupus erythematosus 5%
    • Associations, General
      • Pruritus
      • Hypergammaglobulinaemia
      • ESR high

• anti-PM-Scl (IgG) antibody ⁹
  • Target antigens
    • PM-Scl proteins
      • Location: Exosome; Nucleolar & nuclear protein complex (11 proteins)
      • Exoribonucleases: Involved in the degradation & processing of many different RNA species
      • Exosome: Hereditary disorders
    • PMSCL2 (EXOSC10; PM-Scl-100)
      • Major antigenic protein for many sera
      • Associated with: PM-Scl-associated autoimmune syndromes
    • PMSCL1 (EXOSC9; PM/Scl-75)
      • Common target antigen for PM/Scleroderma overlap syndrome (28%)
      • Mutations: PCH1D
    • Other PM-Scl protein antigenic targets
      • hRrp4p, hRrp40p, hRrp41p, hRrp42p, hRrp46p, hCsl4p
    • Anti-PM-Scl effects on cells
      • Increased expression of long-noncoding RNAs
  • ANA features of antibody
    • Pattern: Homogeneous
    • Location: Nucleolar & Nuclear
  • Epidemiology
    • Common in Polish immune myopathy cohorts
    • Absent in Japan
    • HLA associations
      • HLA-DR3: 75% to 100%
      • HLA-DQB1*02:01
    • Frequency
      • Inflammatory myopathy/Scleroderma overlap syndrome (SSc/Myositis): 24% to 34%
      • Scleroderma (Systemic sclerosis) without myositis: 2%
      • Inflammatory myopathies: 6%
      • PM-Scl antibodies: 43% to 88% have Inflammatory myopathy/Scleroderma overlap syndrome
    • Relation to dsDNA antibodies
      • PM-Scl mainly associated with Myositis & Scleroderma when anti-dsDNA antibodies are absent
    • Systemic sclerosis (SSc; Scleroderma) patients: Associations
      • Younger onset
      • ANA with nucleolar staining
      • Overlap disorders
        • More frequent: Immune myopathies; Pulmonary fibrosis; Calcinosis
        • Less frequent: Peripheral vascular disease; GI disease; Pulmonary arterial hypertension; SLE
        • Limited cutaneous involvement
      • Longer survival
  • Clinical associations
    • General Syndromes
      • Myopathies
        • Immune myopathies & Polymyositis + Scleroderma-like syndrome ³¹
        • PM: Scl-100: B-Cell Inflammatory Myopathies (BCIM) ⁴³
      • Systemic syndromes
        1. Younger age (30 to 50 yrs); SSc Ab; Skin thick; GI; NSIP & ILD
        2. Older age (50 to 60 yrs); NSIP-OP; Mechanic's hands; Relapsing course & better prognosis
        3. Oldest age (> 60 yrs); Muscle; Articular; Undifferentiated connective tissue diseaase
    • Weakness: More in arms
    • Interstitial lung disease: 10% at initial evaluation; 61% at follow-up
    • Skin
      • Mechanic’s hands (80%)
      • Raynaud syndrome (78%)
      • Sclerodactyly (66%)
      • Telangiectasias (66%)
      • Subcutaneous edema (46%)
      • Puffy hands (39%)
    • Esophageal reflux disease (61%)
    • Calcinosis (39%)
    • Telangectasia
    • Other: Arthritis
    • Uncommon: Renal crisis; Finger ulceration
    • Course
      • Treatment: Syndromes often improve with immunosuppression
      • Prognosis: Often good
    • PM/Scl-100 & PM/Scl-75 autoantibodies
      • Many similar features
      • PM-Scl 100: Younger age, Muscle involvement, Calcinosis, Less frequent GI disease
      • IIF: Nucleolar pattern
  • PM-1α (PMSCL2) antibodies ²⁵
    • Onset age: Younger
    • Muscle involvement (Inflammatory): BCIM
    • Calcinosis
    • Inflammatory arthritis
    • Overlap disease
    • Less frequent: Interstitial lung disease; Gastrointestinal symptoms
• anti-Fibrillarin (U3-RNP)
  • ANA: Clumpy nucleolar
  • Antigen: 34 kD protein in U3-RNP particle
  • Clinical association
    • CREST
    • Systemic sclerosis: Skeletal muscle; Small bowel; Pulmonary hypertension
• anti-Ku (IgG) ²³
  • Antigens: 60-70 & 80-86 kD proteins
  • Epidemiology: Antibody occurrence
    • More common in females (86%)
    • Age: Mean 49 to 60 years; Range 8 to 83 ⁵⁵
  • Clinical & Laboratory associations: Varied
    • Muscle: Inflammatory myopathy (33% to 50%)
      • Clinical
        • Myalgia
        • Weakness
          • More with disease progression (40% to 80%)
          • Distal: Hands & Feet
          • Proximal ± Axial
          • Dysphagia (36% to 56%)
        • Paraneoplastic: Rare
        • Associated systemic immune disorders (40%)
        • Treatment: Improvement with corticosteroids
      • Laboratory
        • Serum CK: High (90%); Range 270 to 7,500; Median 2,000
        • Other myositis-associated antibodies: 18%; SRP, Anti-synthetase
        • ANA pattern: Speckled > Nucleolar
      • Muscle Pathology
        • Muscle fiber necrosis: 50%% to 85%
        • HLA Class I & II + muscle fibers: Cytoplasm > Surface
        • Inflammation: 30%; Lymphocyte foci; Perivascular > Endomysial
        • Capillaries: Thick; Large size
        • Vacuoles (60%)
        • C_5b-9: Endomysium; Muscle fiber surfaces
        • Aggregates: p62, BAG3, Myotilin, Immunoproteasomal β5i
    • Skin
      • Raynaud's phenomenon (53% to 79%)
      • Rash (20%)
      • Mechanic's hands (38%)
    • Arthralgias: (62% to 86%)
    • Esophageal dysmotility (35%)
    • Pulmonary
      • Fibrosis (ILD) (40%)
        • More with disease progression
        • Possibly more common with: Ku antibody + High serum CK
        • Often resistant to immunomodulating treatment
      • Pulmonary hypertension
    • Glomerulonephritis
      • More common with: Ku + dsDNA antibody
      • Associated immune disorders: SLE; MCTD
      • Also associated with: Lupus rash; Cytopenia; Anti-RNP antibodies
    • Polyneuropathy (20%): Axonal
    • Cardiac
      • Frequency: Up to 50%
      • Disease progression: Increased frequency
      • Features: Myocarditis: Pericarditis
    • Associated systemic disorders
      • SLE: 20%
      • Japan: Inflammatory myopathy + Scleroderma
      • Systemic sclerosis (SSc)
        • Limited cutaneous form
        • Associated with: ILD

• Double stranded (dsDNA)
• Native: SLE > > other connective tissue disease
• Single stranded
  • 70% in active SLE
  • Many connective tissue disorders
  • ANA: Negative
• In vivo target: Nucleosome

• U1-snRNP
• U2-snRNP
• U3-snRNP
• Sm: SLE
• SSA (Ro) & SSB (La)
• anti-56kD

• Target antigens
  • β₂-glycoprotein I (β2GPI; Apolipoprotein H)
    • Antibodies account for anti-cardiolipin reactivity
    • Associated with lupus anticoagulant activity: Especially IgG
  • Prothrombin (Coagulation factor II)
  • Other antigens
    • Phosphatidyl-ethanolamine/kininogens: Early recurrent pregnancy loss
    • Lamin B1
• Clinical features
  • Vascular thrombosis: Arterial, Venous, or Small vessel; No inflammation
  • Pregnancy morbidity
• Laboratory
  • Anti-cardiolipin antibody
  • Lupus anti-coagulant
• Treatment: Anticoagulation
  • Warfarin
  • Heparin/Low-dose aspirin

• Induce fibroblast activation in vitro
• Present in 46% of patients with Systemic sclerosis (SSc)
• Stimulate monocyte adhesion to fibroblasts by
  • Up-regulation
    • Intercellular adhesion molecule 1 (ICAM-1)
    • Fibroblast secretion of interleukin-1 (IL-1) and monocyte chemotactic protein 1
  • Steady-state increase of messenger RNA for cytokines and chemokines

• General
  • RF definition: Antibodies binding to Fc portion of IgG
  • Other disorders with RF
    • Systemic lupus erythematosus: 15%–35%
    • Sjögren’s syndrome: 20%–30%
    • Cryoglobulinemia: 40%–100%
    • Systemic sclerosis: 20%–30%
    • Polymyositis/dermatomyositis: 5%–10%
    • EGPA: 85%
    • Healthy individuals: 2%–10%
  • Correlations with higher titers
    • Systemic symptoms
    • Vasculitis
    • More severe disease
• IgM: Present in 90% of patients with rheumatoid arthritis
• IgG
  • Present in 65% of patients with rheumatoid arthritis
  • Associated with localized or monoarticular disease
• IgA
  • Present in 65% of patients with rheumatoid arthritis
  • Associated with bone erosions

• Antibodies: Centromere & Fibrillarin
• Neuropathy: Vasculitic (1%)

COMPLEMENT IN HUMAN MUSCLE DISEASE ²

• Membrane attack complex (MAC): Complex of C_5b-9
  • Induces cytolysis
  • Stains Necrotic muscle fibers
  • Main mechanism playing a role in muscle diseases
• Biologic effects of proteolytic fragments of complement
  • Phagocytosis: Opsonization & promotion
  • Inflammation mediated by anaphylotoxins (fragments of C3, C4 & C5): Activation
  • Immune complexes: Solubilization & phagocytic clearance
  • Leukocyte recruitment: C3a, C4a, C5a
  • Phagocytosis enhancement:
    • C3b, C4b, iC3b, vitronectin interact with complement receptors

• Necrosis of muscle fibers in myopathies
  • MAC binding: Intracellular organelles
  • Complement activation:
    • ? alternative pathway
    • Possibly facilitated by Ca⁺⁺-active neutral proteases
  • Effects
    • Removal of necrotic debris
    • Allows myofiber regeneration
• Damage to post synaptic membranes in myasthenia gravis
  • MAC binding: Post-synaptic membrane
  • Associated with IgG binding
  • Effects
    • Simplification of post-synaptic membrane folding
    • Reduction in # of AChRs
    • Widening of synaptic cleft
• HIEM
  • C_5b-9 staining of: Endoneurial microvessels ± Endomysial capillaries
• Dermatomyositis (DM-VP)
  • MAC binding: Endomysial capillaries
  • IV Ig treatment: Reduces MAC binding
  • Effect: Perifascicular myopathy
• Necrotizing myopathy + Pipestem capillaries
  • MAC binding: Capillaries
  • Effect: Necrotic myofibers
• Paraneoplastic necrotic myopathy
  • MAC binding: Necrotic myofibers
• X-linked vacuolated myopathy (XMEA)
  • MAC binding
    • Sarcolemma & internal vacuoles; Granular appearance
    • Vessels
  • Effect: Shedding of sarcolemma into internal vesicles
• Multifocal Motor Neuropathy: IgM vs GM1
• Complement factor C2 deficiency
  • ? Associated with increased frequency of
    • Penicillamine-induced polymyositis
    • Spontaneous polymyositis: HLA-A25, B18, C2 null DR2 supratype

• Bacterial infections: Recurrent
• Lupus erythematosis, Systemic
• Angioedema
• Hemmolytic uremic syndrome, Atypical
• Menbranoproliferative Glomerulonephritis
• Paroxysmal Nocturnal Hemoglobinuria

Myopathies: Antibody Testing Laboratories

• Myositis-specific antibodies are evaluated at:
  • RDL: Extensive MSA panel
    
  • Oklahoma Medical Research Foundation: Extensive MSA panel
    
  • Neuromuscular Clinical Laboratory; Washington University, St. Louis: Myositis-related antibody panel