Internal MedicineInternal MedicineClinical Pathological Clinical Pathological

ConferenceConference

July 18, 2008July 18, 2008

Diagnostic ProcedureDiagnostic Procedure

Right thigh skeletal muscle biopsyRight thigh skeletal muscle biopsy

Further Evaluation:Further Evaluation:

TESTTEST REFERENCE REFERENCE RANGERANGE

Anti- RNP abAnti- RNP ab NegativeNegative NegativeNegative

RF (U/mL)RF (U/mL) <15<15 <10<10

CCP IgG abCCP IgG ab <20<20 2424

Anti Jo-1 abAnti Jo-1 ab 0-1 negative0-1 negative >6>6

Anti SS-A abAnti SS-A ab NegativeNegative NegativeNegative

Anti SS-B abAnti SS-B ab NegativeNegative NegativeNegative

Anti Smith abAnti Smith ab NegativeNegative NegativeNegative

Anti Scl-70 abAnti Scl-70 ab NegativeNegative NegativeNegative

Further Evaluation:Further Evaluation: ThoracentesisThoracentesis

• Transudative fluidTransudative fluid

AFB sputum negative x 3AFB sputum negative x 3

EMGEMG• Sensory and motor neuropathy, but cannot exclude Sensory and motor neuropathy, but cannot exclude

myopathymyopathy

Modified Barium Swallow ExaminationModified Barium Swallow Examination• Moderate dyshphagia with unilateral left pharyngeal Moderate dyshphagia with unilateral left pharyngeal

weaknessweakness

Key Features:Key Features:

ClinicalClinical• Proximal muscle Proximal muscle

weaknessweakness• ArthralgiaArthralgia• DysphagiaDysphagia• Absence of rashAbsence of rash

RadiologyRadiology• Bilateral interstitial Bilateral interstitial

fibrosisfibrosis• Transudative effusionTransudative effusion

LaboratoryLaboratory• Elevated creatine kinaseElevated creatine kinase• Elevated Anti-Jo1Elevated Anti-Jo1• Elevated ESR, CRPElevated ESR, CRP• TransaminitisTransaminitis

EMGEMG• NeuropathyNeuropathy

Idiopathic Inflammatory MyopathyIdiopathic Inflammatory Myopathy

Subclassified Subclassified • PolymyositisPolymyositis• DermatomyositisDermatomyositis• Inclusion body myositisInclusion body myositis

Histological: endomysial inflammation and Histological: endomysial inflammation and activation of the immune response activation of the immune response

Idiopathic Inflammatory MyopathyIdiopathic Inflammatory Myopathy

EpidemiologyEpidemiology• Annual incidence: 2-10 per millionAnnual incidence: 2-10 per million

• Polymyositis: Polymyositis: Disease of adult; rare in people younger than 20 years oldDisease of adult; rare in people younger than 20 years old

• Dermatomyositis:Dermatomyositis: Two peaks: 5-10 years old and 50 years oldTwo peaks: 5-10 years old and 50 years old Female to male – 2:1Female to male – 2:1

• Inclusion body myositisInclusion body myositis Older than 50 years of ageOlder than 50 years of age

Polymyositis/DermatomyositisPolymyositis/Dermatomyositis Diagnostic criteria, Bohan and Diagnostic criteria, Bohan and

Peter, 1975Peter, 1975

1.1. Symmetrical, proximal muscle Symmetrical, proximal muscle weaknessweakness

2.2. Elevation of serum skeletal muscle Elevation of serum skeletal muscle enzymes enzymes

CK, LDH, AST, ALT, and AldolaseCK, LDH, AST, ALT, and Aldolase

3.3. Muscle biopsy with evidence of Muscle biopsy with evidence of myositismyositis

4.4. EMG pattern of myopathyEMG pattern of myopathy

5.5. Typical rash of dermatomyositis- Typical rash of dermatomyositis- photosensitive rash, heliotrope photosensitive rash, heliotrope rash, and gottron papulesrash, and gottron papules

Gottron Papules

Heliotrope rash

Polymyositis/ DermatomyositisPolymyositis/ Dermatomyositis Esophageal involvement (8-30%), inflammation of Esophageal involvement (8-30%), inflammation of

cardiac muscle cardiac muscle

Interstitial Lung disease (50%)Interstitial Lung disease (50%)• Nonspecific interstitial pneumonia (NSIP)Nonspecific interstitial pneumonia (NSIP)• Usual interstitial pneumonia (UIP)Usual interstitial pneumonia (UIP)

Anti-Jo 1 and Anti-Mi2Anti-Jo 1 and Anti-Mi2• Anti- Jo-1 commonly have Interstitial lung diseaseAnti- Jo-1 commonly have Interstitial lung disease• Anti-M1 have skin findingsAnti-M1 have skin findings

Increase cancer riskIncrease cancer risk• 7-10% of polymyositis7-10% of polymyositis• 15-20% of dermatomyositis15-20% of dermatomyositis

Polymyositis/ DermatomyositisPolymyositis/ Dermatomyositis

Cellular immunityCellular immunity• Polymyositis- Class II HLA antigen DR3, Polymyositis- Class II HLA antigen DR3,

predominant CD8 T cells predominant CD8 T cells

• Dermatomyositis- Predominant B cells Dermatomyositis- Predominant B cells and CD4 T cells in inflammatory and CD4 T cells in inflammatory infiltratesinfiltrates

Inclusion Body MyositisInclusion Body Myositis May be asymmetric and involves May be asymmetric and involves

distal musclesdistal muscles

Dysphagia is prominent( 40-80%)Dysphagia is prominent( 40-80%)

Muscle enzyme is only mildly Muscle enzyme is only mildly elevatedelevated

EMG- Myopathic and Neuropathic EMG- Myopathic and Neuropathic

Biopsy- mononuclear infiltrates and Biopsy- mononuclear infiltrates and red-rimmed vacuoles in muscle cells red-rimmed vacuoles in muscle cells with inclusion bodieswith inclusion bodies

Mild response to conventional Mild response to conventional steroid treatmentsteroid treatment

Inclusion Body Myositis: Inclusion Body Myositis: PathogenesisPathogenesis

Engel and Arahata 1984Engel and Arahata 1984

• Endomysial infiltrates are composed of Endomysial infiltrates are composed of primarily CD8+ T Cellsprimarily CD8+ T Cells

Engela and Engel 1988; Orimo 1994; Schmidt 2004Engela and Engel 1988; Orimo 1994; Schmidt 2004

• CD8+ T Cells surrounds MHC class I CD8+ T Cells surrounds MHC class I myofibers and express perforinmyofibers and express perforin

Cupler 1996; Saperstien 1999; Tsuruta 2001; Dalakas 2006Cupler 1996; Saperstien 1999; Tsuruta 2001; Dalakas 2006

• Association with chronic viral infection Association with chronic viral infection

Inclusion Body Myositis: Inclusion Body Myositis: PathogenesisPathogenesis

Hypothesis- Dalakas 2006Hypothesis- Dalakas 2006

Disease begins with viral infectionDisease begins with viral infection HIV, HTLV-1, Hepatitis CHIV, HTLV-1, Hepatitis C

1.1. Clonal expansion of CD 8+ T cells and T-cell mediated, MHC class I Clonal expansion of CD 8+ T cells and T-cell mediated, MHC class I cytotoxicity via perforin pathway leading to necrosiscytotoxicity via perforin pathway leading to necrosis

2.2. Cytokines upregulate MHC class I molecules leading to MHC-peptide loading Cytokines upregulate MHC class I molecules leading to MHC-peptide loading complex and endoplasmic reticulum (ER) stress complex and endoplasmic reticulum (ER) stress

3.3. ER stress leads to activation of transcription factor NFkB, further stimulating ER stress leads to activation of transcription factor NFkB, further stimulating MHC/CD 8 complex and induce a self-sustain inflammatory responseMHC/CD 8 complex and induce a self-sustain inflammatory response

Dalakas, 2006

TreatmentTreatment

Polymyositis/ DermatomyositisPolymyositis/ Dermatomyositis• High dose corticosteroids- respond within 6 High dose corticosteroids- respond within 6

weeksweeks• Methotrexate, cyclosporine, and IVIGMethotrexate, cyclosporine, and IVIG

Inclusion body myositisInclusion body myositis• Most immunotherapeutic agents are Most immunotherapeutic agents are

ineffectiveineffective

Age appropriate cancer screeningAge appropriate cancer screening

FINAL DIAGNOSIS:FINAL DIAGNOSIS:

Inclusion Body MyositisInclusion Body Myositis

Dermatomyositis sine Dermatomyositis sine dermatitisdermatitis

Viral Infection

Proximal muscle Weakness,

myalgiaDysphagiaCough

Interstitial lung disease

Elevated serum muscle enzymes Rash

Complex with MHC class I Cytotoxicity via perforin

pathway causing necorsis

Skeletal muscle inflammation

RecurrentAspiration

Clonal expansion of CD 8+ T Cell Cytokine release

Inclusion Body Myositis Dermatomyositis

Endoplasmic reticulum stress and

Intracellular peptide loading complex

B cells and CD4 T cells in B cells and CD4 T cells in

inflammatory infiltratesinflammatory infiltrates

Skeletal muscle inflammation

Epidermal and dermal

destruction

Pathogenesis of Patient’s disease

Case Follow-upCase Follow-up Patient was started on empiric antibiotics Patient was started on empiric antibiotics

for aspiration pneumoniafor aspiration pneumonia

Started on prednisone 30mg bidStarted on prednisone 30mg bid

Pt transferred to subacute inpatient Pt transferred to subacute inpatient rehabilitationrehabilitation

CPK=5675, AST=237, ALT=252 after one CPK=5675, AST=237, ALT=252 after one week of prednisone therapyweek of prednisone therapy

Pt with improvement in deltoid strength Pt with improvement in deltoid strength and proximal muscle strengthand proximal muscle strength

Case Follow-upCase Follow-up Eventually discharged with outpatient Eventually discharged with outpatient

rheumatology follow uprheumatology follow up

Initially, clinical symptoms improved and patient Initially, clinical symptoms improved and patient was maintained on daily steroid for about 1 yearwas maintained on daily steroid for about 1 year

Patient was found to have rising CK, and Patient was found to have rising CK, and Azathioprine was added to his regimenAzathioprine was added to his regimen

Azathioprine did not improve his CK levels, and Azathioprine did not improve his CK levels, and was switched to Mycophenolate mofetil was switched to Mycophenolate mofetil

Patient was electively admitted 2 weeks ago for Patient was electively admitted 2 weeks ago for IVIG as CK levels continue to be elevatedIVIG as CK levels continue to be elevated

THANK YOU!THANK YOU! Medical Student DiscussantsMedical Student Discussants

Michael Goldman Michael Goldman Juan LadoJuan LadoMegan McgillMegan McgillNekee PandyaNekee Pandya

Moderator: Martin Blaser, MDModerator: Martin Blaser, MD Faculty Discussant: Peter Izmirly, MDFaculty Discussant: Peter Izmirly, MD Radiology Speaker: Dr. David Naidich , MDRadiology Speaker: Dr. David Naidich , MD Pathology Speaker: David Zagzag, MDPathology Speaker: David Zagzag, MD

SPECIAL THANKS: Christina Yoon , MD, SPECIAL THANKS: Christina Yoon , MD, Harry Harry Shen, MD and Shen, MD and Jean Park, M.D.Jean Park, M.D.