Internal Medicine Clinical Pathological Conference July 18, 2008

Diagnostic Procedure Right thigh skeletal muscle biopsy Right thigh skeletal muscle biopsy

Further Evaluation: TEST REFERENCE RANGE Anti- RNP ab NegativeNegative RF (U/mL) <15<10 CCP IgG ab <2024 Anti Jo-1 ab 0-1 negative >6 Anti SS-A ab NegativeNegative Anti SS-B ab NegativeNegative Anti Smith ab NegativeNegative Anti Scl-70 ab NegativeNegative

Further Evaluation: Thoracentesis Thoracentesis Transudative fluidTransudative fluid AFB sputum negative x 3 AFB sputum negative x 3 EMG EMG Sensory and motor neuropathy, but cannot exclude myopathy Sensory and motor neuropathy, but cannot exclude myopathy Modified Barium Swallow Examination Modified Barium Swallow Examination Moderate dyshphagia with unilateral left pharyngeal weaknessModerate dyshphagia with unilateral left pharyngeal weakness

Key Features: Clinical Clinical Proximal muscle weaknessProximal muscle weakness ArthralgiaArthralgia DysphagiaDysphagia Absence of rashAbsence of rash Radiology Radiology Bilateral interstitial fibrosisBilateral interstitial fibrosis Transudative effusionTransudative effusion Laboratory Laboratory Elevated creatine kinase Elevated Anti-Jo1 Elevated ESR, CRP Transaminitis EMG EMG Neuropathy

Idiopathic Inflammatory Myopathy Subclassified Subclassified PolymyositisPolymyositis DermatomyositisDermatomyositis Inclusion body myositisInclusion body myositis Histological: endomysial inflammation and activation of the immune response Histological: endomysial inflammation and activation of the immune response

Idiopathic Inflammatory Myopathy Epidemiology Epidemiology Annual incidence: 2-10 per millionAnnual incidence: 2-10 per million Polymyositis:Polymyositis: Disease of adult; rare in people younger than 20 years old Disease of adult; rare in people younger than 20 years old Dermatomyositis:Dermatomyositis: Two peaks: 5-10 years old and 50 years old Two peaks: 5-10 years old and 50 years old Female to male – 2:1 Female to male – 2:1 Inclusion body myositisInclusion body myositis Older than 50 years of age Older than 50 years of age

Polymyositis/Dermatomyositis Diagnostic criteria, Bohan and Peter, 1975 Diagnostic criteria, Bohan and Peter, Symmetrical, proximal muscle weakness 2.Elevation of serum skeletal muscle enzymes CK, LDH, AST, ALT, and Aldolase CK, LDH, AST, ALT, and Aldolase 3.Muscle biopsy with evidence of myositis 4.EMG pattern of myopathy 5.Typical rash of dermatomyositis- photosensitive rash, heliotrope rash, and gottron papules Gottron Papules Heliotrope rash

Polymyositis/ Dermatomyositis Esophageal involvement (8-30%), inflammation of cardiac muscle Esophageal involvement (8-30%), inflammation of 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-Mi2 Anti-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 risk Increase cancer risk 7-10% of polymyositis7-10% of polymyositis 15-20% of dermatomyositis15-20% of dermatomyositis

Polymyositis/ Dermatomyositis Cellular immunity Cellular immunity Polymyositis- Class II HLA antigen DR3, predominant CD8 T cellsPolymyositis- Class II HLA antigen DR3, predominant CD8 T cells Dermatomyositis- Predominant B cells and CD4 T cells in inflammatory infiltratesDermatomyositis- Predominant B cells and CD4 T cells in inflammatory infiltrates

Inclusion Body Myositis May be asymmetric and involves distal muscles May be asymmetric and involves distal muscles Dysphagia is prominent( 40-80%) Dysphagia is prominent( 40-80%) Muscle enzyme is only mildly elevated Muscle enzyme is only mildly elevated EMG- Myopathic and Neuropathic EMG- Myopathic and Neuropathic Biopsy- mononuclear infiltrates and red-rimmed vacuoles in muscle cells with inclusion bodies Biopsy- mononuclear infiltrates and red-rimmed vacuoles in muscle cells with inclusion bodies Mild response to conventional steroid treatment Mild response to conventional steroid treatment

Inclusion Body Myositis: Pathogenesis Engel and Arahata 1984 Engel and Arahata 1984 Endomysial infiltrates are composed of primarily CD8+ T CellsEndomysial infiltrates are composed of primarily CD8+ T Cells Engela and Engel 1988; Orimo 1994; Schmidt 2004 Engela and Engel 1988; Orimo 1994; Schmidt 2004 CD8+ T Cells surrounds MHC class I myofibers and express perforinCD8+ T Cells surrounds MHC class I myofibers and express perforin Cupler 1996; Saperstien 1999; Tsuruta 2001; Dalakas 2006 Cupler 1996; Saperstien 1999; Tsuruta 2001; Dalakas 2006 Association with chronic viral infectionAssociation with chronic viral infection

Inclusion Body Myositis: Pathogenesis Hypothesis- Dalakas 2006 Hypothesis- Dalakas 2006 Disease begins with viral infection HIV, HTLV-1, Hepatitis C HIV, HTLV-1, Hepatitis C 1.Clonal expansion of CD 8+ T cells and T-cell mediated, MHC class I cytotoxicity via perforin pathway leading to necrosis 2.Cytokines upregulate MHC class I molecules leading to MHC-peptide loading complex and endoplasmic reticulum (ER) stress 3.ER stress leads to activation of transcription factor NFkB, further stimulating MHC/CD 8 complex and induce a self-sustain inflammatory response Dalakas, 2006

Treatment Polymyositis/ Dermatomyositis Polymyositis/ Dermatomyositis High dose corticosteroids- respond within 6 weeksHigh dose corticosteroids- respond within 6 weeks Methotrexate, cyclosporine, and IVIGMethotrexate, cyclosporine, and IVIG Inclusion body myositis Inclusion body myositis Most immunotherapeutic agents are ineffective Most immunotherapeutic agents are ineffective Age appropriate cancer screening Age appropriate cancer screening

FINAL DIAGNOSIS: Inclusion Body Myositis Dermatomyositis sine dermatitis

Viral Infection Proximal muscle Weakness, myalgia DysphagiaCough Interstitial lung disease Elevated serum muscle enzymes Rash Complex with MHC class I Cytotoxicity via perforin pathway causing necorsis Skeletal muscle inflammation Recurrent Aspiration 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 inflammatory infiltrates Skeletal muscle inflammation Epidermal and dermal destruction Pathogenesis of Patient’s disease

Case Follow-up Patient was started on empiric antibiotics for aspiration pneumonia Patient was started on empiric antibiotics for aspiration pneumonia Started on prednisone 30mg bid Started on prednisone 30mg bid Pt transferred to subacute inpatient rehabilitation Pt transferred to subacute inpatient rehabilitation CPK=5675, AST=237, ALT=252 after one week of prednisone therapy CPK=5675, AST=237, ALT=252 after one week of prednisone therapy Pt with improvement in deltoid strength and proximal muscle strength Pt with improvement in deltoid strength and proximal muscle strength

Case Follow-up Eventually discharged with outpatient rheumatology follow up Eventually discharged with outpatient rheumatology follow up Initially, clinical symptoms improved and patient was maintained on daily steroid for about 1 year Initially, clinical symptoms improved and patient was maintained on daily steroid for about 1 year Patient was found to have rising CK, and Azathioprine was added to his regimen Patient was found to have rising CK, and Azathioprine was added to his regimen Azathioprine did not improve his CK levels, and was switched to Mycophenolate mofetil Azathioprine did not improve his CK levels, and was switched to Mycophenolate mofetil Patient was electively admitted 2 weeks ago for IVIG as CK levels continue to be elevated Patient was electively admitted 2 weeks ago for IVIG as CK levels continue to be elevated

THANK YOU! Medical Student Discussants Medical Student Discussants Michael Goldman Michael Goldman Juan Lado Megan Mcgill Nekee Pandya Moderator: Martin Blaser, MD Moderator: Martin Blaser, MD Faculty Discussant: Peter Izmirly, MD Faculty Discussant: Peter Izmirly, MD Radiology Speaker: Dr. David Naidich, MD Radiology Speaker: Dr. David Naidich, MD Pathology Speaker: David Zagzag, MD Pathology Speaker: David Zagzag, MD SPECIAL THANKS: Christina Yoon, MD, Harry Shen, MD and Jean Park, M.D. SPECIAL THANKS: Christina Yoon, MD, Harry Shen, MD and Jean Park, M.D.