John J. Cush, MD Chief, Rheumatology

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John J. Cush, MDChief, Rheumatology Clinical
ImmunologyPresbyterian Hospital of
DallasClinical Professor of Internal MedicineUT
Southwestern Medical School

• St. John's University, B.S. 1977
• SGUSOM, MD July 1981
• Internal Medicine Residency 81-84
• Chief Medical Resident 83-84
• Rheumatology Fellowship
• Parkland Memorial Hospital, 84 - 87
• ECFMG, 1980 FLEX (I-III), 1981
• License GA, NY, TX 1989
• Diplomate in Internal Medicine, 1984
• Diplomate in Rheumatology, 1988
• UTSWMC Faculty 87- present
• Chairman, Int Medicine SGU, 2004-

• Intern of the Year - Coney Island 1982
• Chief Medical Resident 1984
• Best Doctors In America 1996-2005
• Teacher of the Year - PHD 1998-99
• Best Doctors in Dallas 2002-05
• Arthritis Foundation, Chairman, Prof, Educ
• American College of Rheumatology
• FDA Arthritis Advisory Committee 2002 -
• St. Georges University School of Medicine
• Chairman, Academic Board 1990 -
• Trustee, Board of Trustee's 1993
• 100 Publications
• 2 Books

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The TEST

• Lectures Big picture gt stressed gt anything
  covered
• Syllabus yes its dense with info. Look for
  overlap.
• Lectures Syllabus synergistic importance
• Common presentations, Common Disorders
• Common presentations of Uncommon Disorders
• Wont do Rare Presentations of Rare Disorders
• Pathogenesis
• Clinical manifestations Outcome
• Basic Treatment Decisions
• 6-8 Questions

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Rheumatology Programme

• Tuesday 4/12
• !st Hr Evaluation of Rheumatic Patient
• Laboratory testing rheumatic pts
• 2nd Hr SLE
• Osteoarthritis vs Rheumatoid arthritis
• Wednesday AM
• 3rd Hr Gout, Pseudogout,
• Juvenile arthritis, Rheumatic Fever
• 4th Hr Spondyloarthropathies AS, Reactive,
  Psoriatic, IBD
• Wednesday PM
• 5th Hr myositis, Scleroderma, Fibromyalgia,
  Carpal Tunnel
• Thursday
• 6th Hr Vasculitis
• Infectious Arthritis, Lyme Disease
• 7th Hr Anti-Rheumatic Drugs
• Test questions/review

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Rheumatology

• Int. Medicine (3yrs) 2 yrs Rheumatology,
  fellowship
• Specialize in
• Musculoskeletal disorders Medical management,
  surgical indications coordinate adjunctive care
  (OT, PT, Vocational)
• Autoimmune disorders
• Clinical Immunologists
• Clinical Pharmacologists rheumatologists
  specialize in immunosuppressive,
  immunomodulatory, cytotoxic therapies
• Whats the average age in rheumatology clinic?
• 70 million affected
• Only 3,200 Board Certified Rheumatologists in USA
  (???)

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Rheumatologic Assessments

• What is needed to establish a differential
  diagnosis
• Consider the most common conditions
• Diagnosis by
• Age, Sex, Race
• Type of presentation Febrile, Acute, Chronic,
  Widespread pain
• Number of Joints
• LABS DO NOT MAKE A DIAGNOSIS HP DOES!
• How can labs lead you astray?
• ESR/CRP Origins and associations
• Serologies (RF, ANA, CCP, APL, ANCA) when to do
• in what OTHER diseases are they positive?
• Arthrocentesis for diagnosis

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Common Causes of Joint Pain

• Musculoskeletal conditions gt 70 million
• 315 million MD office visits (Disability 17
  million)
• Low Back Pain gt 5 million per year
• Trauma/Fracture
• Osteoarthritis 12-20 million
• Repetitive strain/injury
• Bursitis,TendinitisCarpal tunnel syndrome 2.1
  million
• Fibromyalgia 3.7 million
• Rheumatoid Arthritis 2.1-2.5 million
• Gout, Pseudogout 2 million
• Spondyloarthropathy AS, PsA, Reactive, IBD
  arthritis (1.4 mil)
• Polymyalgia rheumatica/temporal arteritis
• Infectious arthritis

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Uncommon Causes of Joint Pain

• Systemic lupus erythematosus 239,000
• Drug-induced lupus
• Scleroderma / CREST lt 50,000
• Mixed Connective Tissue Disease (MCTD)
• Vasculitis (Polyarteritis nodosa, Wegeners
  granulomatosus)
• Inflammatory myositis lt50,000
• Juvenile arthritis
• Behcets syndrome
• Sarcoidosis
• Relapsing polychrondritis
• Stills Disease

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Goals of Assessment

• Identify Red Flag conditions
• Conditions with sufficient morbidity/mortality to
  warrant an expedited diagnosis
• Make a timely diagnosis
• Common conditions occur commonly
• Many MS conditions are self-limiting
• Some conditions require serial evaluation over
  time to make a Dx
• Provide relief, reassurance and plan for
  evaluation and treatment

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RED FLAG CONDITIONS

• FRACTURE
• SEPTIC ARTHRITIS
• GOUT/PSEUDOGOUT

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Key Questions

• Inflammatory vs. Noninflammatory ?
• Acute vs. Chronic ? (lt or gt 6 weeks)
• Articular vs. Periarticular ?
• Mono/Oligoarthritis vs Polyarthritis ?
• (Focal) (Widespread)
• Are there RED FLAGS?

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Inflammatory vs Noninflammatory
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Articular vs. Periarticular

• Finding ARTICULAR PERIARTICULAR
• Pain Diffuse, deep "point" tenderness
• ROM Pain Activepassive Active motion
• in all planes in few planes
• Swelling Common Uncommon

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Mono/Oligo vs Polyarticular

• Monarticular
• Osteoarthritis
• Fracture
• Osteonecrosis
• Gout or Pseudogout
• Septic arthritis
• Lyme disease
• Reactive arthrtis
• Tuberculous/Fungal arthritis
• Sarcoidosis

• Polyarticular
• Osteoarthritis
• Rheumatoid arthritis
• Psoriatic arthritis
• Viral arthritis
• Serum Sickness
• Juvenile arthritis
• SLE/PSS/MCTD

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Nonarticular Pain

• Fibromyalgia
• Fracture
• Bursitis, Tendinitis, Enthesitis, Periostitis
• Carpal tunnel syndrome
• Polymyalgia rheumatica
• Sickle Cell Crisis
• Raynauds phenomenon
• Reflex sympathetic dystrophy
• Myxedema

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Formulating a Differential Dx
Articular Nonarticular
Inflammatory Septic Gout Rheumatoid arthritis Psoriatic arthritis Bursitis Enthesitis PMR Polymyositis
Noninflammatory Osteoarthritis Charcot Joint Fracture Fibromyalgia Carpal tunnel RSD
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Musculoskeletal Complaint
lt 55 yrs.
gt 55 yrs.
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History Clues to Diagnosis

• Age
• Young JRA, SLE, Reiter's, GC arthritis
• Middle Fibromyalgia, tendinitis, bursitis, LBP
  RA
• Elderly OA, crystals, PMR, septic, osteoporosis
• Sex
• Males Gout, AS, Reiter's syndrome
• Females Fibrositis, RA, SLE, osteoarthritis
• Race
• White PMR, GCA and Wegener's
• Black SLE, sarcoidosis
• Asian RA, SLE, Takayasu's arteritis, Behcet's

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Onset Chronology

• Acute Fracture, septic arthritis, gout,
  rheumatic fever, Reiter's syndrome
• Chronic OA, RA, SLE, psoriatic arthritis,
  fibromyalgia
• Intermittent gout, pseudogout, Lyme, Familial
  Mediterranean Fever
• Additive OA, RA, psoriatic
• Migratory Viral arthritis (hepatitis B),
  rheumatic fever, GC arthritis

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Drug Induced Syndromes

• Myalgias/myopathy Steroids, lovastatin, statins,
  clofibrate, alcohol, cocaine
• Gout Diuretics, ASA, cytotoxics, cyclosporine,
  alcohol, moonshine
• Drug-induced lupus hydralazine, procainamide,
  quinidine, INH phenytoin, chlorpromazine, TCN,
  TNF inhibitors
• Osteopenia Steroids, chronic heparin, phenytoin
• Osteonecrosis Steroids, alcohol, radiation
  therapy

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Rheumatic Review of Systems

• Constitutional fever, wt loss, fatigue
• Ocular blurred vision, diplopia, conjunctivitis,
  dry eyes
• Oral dental caries, ulcers, dysphagia, dry mouth
• GI hx ulcers, Abd pain, change in BM, melena,
  jaundice
• Pulm SOB, DOE, hemoptysis, wheezing
• CVS angina/CP, arrhythmia, HTN, Raynauds
• Skin photosensitivity, alopecia, nails, rash
• CNS HA, Sz, weakness, paraesthesias
• Reproductive sexual dysfunction, promiscuity,
  genital lesions, miscarriages, impotence
• MS joint pain/swelling, stiffness, ROM/function,
  nodules

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Rheumatic Review of Systems

• Fever/Constitutional septic arthritis,
  vasculitis, Stills disease
• Ocular Reiters, Behcets, Sjogrens, Cataracts
  (steroids)
• Oral Sjogrens, Lupus, GC, myositis, drugs
• GI Reactive arthritis, IBD, hepatitis,
  Polyarteritis, Scleroderma
• Pulm SLE, RA lung, Churg-Strauss, Wegeners,
  Scleroderma
• CVS Vasculitis, PSS, Raynauds, antiphospholipid
  syndrome
• Skin SLE, psoriatic, vasculitis, Kawasaki
  syndrome
• CNS lupus carpal tunnel, antiphospholipid,
  vasculitis
• GYN/GU antiphospholipid, SLE, Reiters, Behcets,
  CTX
• Musculoskeletal Gout, RA, OA, fibromyalgia,
  fracture

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Musculoskeletal Exam

• Observe patient function (walk, write, turn,
  rise, etc)
• Identify articular vs. periarticular vs.
  extraarticular
• Detailed recording of joint exam (eg, tender
  joints)
• Specific maneuvers
• Tinels sign? Median N.? Carpal Tunnel syndrome
• Phalens sign ? Median N.? Carpal Tunnel syndrome
• Bulge sign ? Syn.Fluid Suprapatellar pouch? Knee
  effusion
• Drop arm sign ?Complete Rotator Cuff Tear?Trauma?
• McMurray sign ?Torque on Meniscus ? Cartilage Tear

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Right Joint Left
TMJ
SC
AC
Shoulder
Elbow
Wrist
CMC1
MCP 1-5
PIP 1-5
Hip
Knee
Ankle
Tarsus
MTP 1-5
Toe 1-5
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RHEUMATOSCREEN PLUS
?

• CBC differential
• Chem-20
• Uric acid
• Urinalysis
• ESR
• C-reactive protein
• RPR
• CPK
• Aldolase
• ASO
• Immune complexs
• TFTs w/ TSH

• IgM- RF
• ANA
• ENA (SSA, SSB, RNP, Sm)
• dsDNA-Crithidia
• Scl-70, Jo-1
• Histone Abs
• Ribosomal P Ab
• Coombs
• C3, C4
• CH50
• Cryoglobulins

• Lupus anticoag.
• Cardiolipin Ab
• c-ANCA
• anti-PR3, -MPO
• anti-GBM
• SPEP
• Lyme titer
• HIV
• Chlamydia Ab.
• Parvovirus B19
• HBV, HCV, HAV
• HLA typing

CUSHY LABS INC. YOUR INDECISION IS OUR BREAD AND
BUTTER
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Kingstown General Hosp. CheapoScreen
?
CBC diff 35.00 Chem-20
108.00 Urinalysis 30.00 ESR or CRP
25.30 Uric acid 40.00

• ANA
• RF

238.30
CUSHY LABS INC. YOUR INDECISION IS OUR BREAD AND
BUTTER
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Further Investigations

• Many conditions are self-limiting
• Consider when
• Systemic manifestations (fever, wt.loss, rash,
  etc)
• Trauma (do exam or imaging for Fracture, ligament
  tear)
• Neurologic manifestations
• Lack of response to observation symptomatic Rx
  (lt6wks)
• Chronicity ( gt 6 weeks)

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Common Rheumatic Tests

• Tests Sensitivity Specificity
• Rheumatoid 80 95
• Factor
• Antinuclear 98 93
• Antibody
• Uric Acid 63 96

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Acute Phase Reactants

• Erythrocyte Sedimentation Rate (nonspecific)
• C-Reactive Protein (CRP)
• Fibrinogen
• Serum Amyloid A (SAA)
• Ceruloplasmin
• Complement (C3, C4)
• Haptoglobin
• Ferritin
• Other indicators leukocytosis, thrombocytosis,
  hypoalbuminemia, anemia of chronic disease

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Erythrocyte Sedimentation Rate

• ESR Introduced by Fahraeus 1918
• Mechanisms Rouleaux formation
• Characteristics of RBCs
• Shear forces and viscosity of plasma
• Bridging forces of macromolecules. High MW
  fibrinogen tends to lessen the negative charge
  between RBCs and promotes aggregation.
• Methods Westergren method
• Low ESR Polycythemia, Sickle cell, hemolytic
  anemia, hemeglobinopathy, spherocytosis, delay,
  hypofibrinogen, hyperviscosity (Waldenstroms)
• High ESR Anemia, hypercholesterolemia, female,
  pregnancy, inflammation, malignancy,nephrotic
  syndrome

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ESR Age
MAge/2 FAge10/2
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Extreme Elevation of ESRRME Fincher, Arch Int
Med 1461986
Cause ESR gt 100 () ESR 75 99 ()
Infection 14 (33) 6 (16)
Renal Dz 7 (17) 4 (11)
Neoplasm 7 (17) 4 (11)
Inflammatory 6 (14) 6 (16)
Miscellaneous 4 (9.5) 0
Unknown 4 (9.5) 17 (46)
Total 42 (100) 37 (100)
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ACP Recommendations for Diagnostic Use of
Erythrocyte Sedimentation Rate

• The ESR should not be used to screen
  asymptomatic persons for disease
• The ESR should be used selectively and
  interpreted with caution....Extreme elevation of
  the ESR seldom occurs in patients with no
  evidence of serious disease
• If there is no immediate explanation for an
  increased ESR, the physician should repeat the
  test in several months rather than search for
  occult disease
• The ESR is indicated for the diagnosis and
  monitoring of temporal arteritis and polymyalgia
  rheumatica
• In diagnosing and monitoring patients with
  rheumatoid arthritis, the ESR should be used
  prinicipally to resolve conflicting clinical
  evidence
• The ESR may be helpful in monitoring patients
  with treated Hodgkins disease

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Antinuclear Antibodies

• 99.99 of SLE patients are ANA positive
• () ANA is not diagnostic of SLE
• 20 million Americans are ANA
• 239,000 SLE patients in the USA
• Normals 5 ANA Elderly 15 ANA
• Significance rests w/ Clinical Hx, titer, pattern
• Higher the titer, the greater the suspicion of SLE

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• ANA PATTERN Ag Identified Clinical Correlate
  
• Diffuse DeoxyRNP Low titerNonspecific
• Histones Drug-induced lupus
• Peripheral ds-DNA 50 of SLE (specific)
• Speckled U1-RNP gt90 of MCTD
• Sm 30 of SLE (specific)
• Ro (SS-A) Sjogrens 60, SCLE
• Neonatal LE, ANA(-)LE
• La (SS-B) 50 Sjogrens, 15 SLE
• Scl-70 40 of PSS (diffuse dz)
• PM-1 PM/DM
• Jo-1 PM, Lung Dz, Arthritis
• Nucleolar RNA Polymerase I, others 40 of
  PSS
• Centromere Kinetochore 75 CREST (limited dz)
• Cytoplasmic Ro, ribosomal P SS, SLE psychosis

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Antinuclear Antibodies

• Virtually present in all SLE patients
• Not synonymous with a Dx of SLE
• May be present in other conditions
• Drug-induced (procainamide, hydralazine,
  quinidine, TCN, TNF inhib.)
• Age (3X increase gt 65 yrs.)
• Autoimmune disease
• AIHA, Graves, Thyroiditis, RA, PM/DM,
  Scleroderma, Antiphospholipid syndrome
• Chronic Renal or Hepatic disease
• Neoplasia associated
• Ineffective screen for arthritis or lupus
• Specificity enhanced when ordered wisely

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ANA and Odds of SLE
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Frequency in SLE

• Autoantibody Frequency
• dsDNA 30-70
• Sm 20-40
• RNP 40-60
• Ro 10-15
• Ribosomal P 5-10
• Histones 30
• ACA 40-50

Egner W, J Clin Pathol 53424, 2000
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Antiphospholipid Syndrome

• Triad Any TEST plus
• Thrombotic events
• Spontaneous abortion(s)
• Thrombocytopenia
• Others Migraine, Raynauds, Libman-Sacks
  endocarditis, MR, Transverse myelitis, neuropathy
• Ab found in gt30 SLE, other CTD
• Correlates with IgG Ab and B2 Glycoprotein I
• Rx Warfarin, heparin

PTT/LAC
RPR
Cardiolipin
3 Tests
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Rheumatoid Factor
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Rheumatoid Factor

• 80 of RA patients. High titers associated with
  greater disease severity and extraarticular
  disease (NODULES).
• Utility varies with use
• Pre-test probability 1 Pos. Predictive Value
  7
• Pre-test probability 50 Pos. Predictive Value
  88
• Nonrheumatic causes
• Age
• Infection SBE 40, hepatitis 25, MTbc 8,
  syphilis 10, parasitic diseases gt50 (Chagas,
  leishmaniasis, schistosomiasis), leprosy 35,
  viral infection lt50 (rubella, mumps,
  influenza-15-65)
• Pulmonary Dz Sarcoid lt30, IPF lt50, Silicosis
  40, Asbestosis 30
• Malignancy 20
• Primary Biliary Cirrhosis 50-75
• 20 of RA patients are seronegative for RF

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Age and Serologic Testing
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Anti- Citrullinated Cyclic Peptides (CCP)

• RF only in 20-50 of Early RA patients
• Antibodies against Filaggrin (AFA), Keratin
  (AKA), anti-Perinuclear Factor (APF) directed
  against skin Ag profilaggrin - shown to be
  specific for RA, not popular, difficult to assay
• Citrulline enzymatically post-translationally
  modified arginine
• CCP a peptide variant of citrulline-rich
  filaggrin epitopes
• CCP Abs thought to represent AKA, APF,
  anti-fillagrin Abs
• As Sensitive as RF (40-66)
• Very Specific for RA (Specificity 98)
• Correlates with
• Early RA, aggressive Dz,
• ? risk of Xray damage, shared epitopes
• Patients w/ Shared Epitope have enhanced response
  to citrulline self-peptides ? CCP may contribute
  to RA pathogenesis

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CCP antibodies by ELISA
AITD autoimmune thyroid dz MGUS-monoclonal
gammopathy NC-normals
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ANCA Anti-Neutrophil Cytoplasmic
Antibodies

• C-ANCA, P-ANCA, myeloperoxidase (MPO),
  proteinase-3 (PR3)
• ANCA antibodies that bind to enzymes present in
  the cytoplasm of neutrophils. Associated with
  several types of vasculitis.
• C-ANCA cytoplasmic staining. 50 to 90
  sensitivity for Wegener's
• P-ANCA exhibits perinuclear staining. Less
  specific, 60 of patients with microscopic
  polyarteritis and Churg-Straus syndrome.

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Serum Uric Acid Incidence of Gout
Serum Urate mg/dl Gout Incidence/yr/1000 5 year cummulative
lt 7.0 0.8 5
7.0 7.9 0.9 6
8.0 8.9 4.1 9.8
gt 9.0 49 220
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HLA-B27

• Class I MHC Ag, associated with the
  spondyloarthropathies
• Ankylosing spondylitis, Reiter's syndrome,
  Psoriatic arthritis, and enteropathic arthritis.
• HLA-27 is found in up to 8 of normals
• 3-4 of African-Americans, 1 of Orientals.
• Increased risk of spondylitis and uveitis.
• Indications may be used infrequently as a
  diagnostic test in AS, Reiters, Psoriatic
  arthritis

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Indications for Arthrocentesis

• Monarthritis (acute or chronic)
• Suspected infection or crystal-induced arthritis
• New monarthritis in old polyarthritis
• Joint effusion and trauma
• Intrarticular therapy or Arthrography
• Uncertain diagnosis

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Synovial Fluid Analysis

• Visual inspection (color, clarity, hemorrhagic)
• Viscosity
• - incr w/ normal (noninflam) SF (long string
  sign)
• - decreased with inflammatory SF (loss of string
  sign)
• Place in tubes EDTA (purple)-cell count.
  Na
  heparin (green)-Crystals
• Cell Count and Differential
• noninflammatory WBC lt 2000/mm3 (PMNs lt 75)
• inflammatory WBC 2000 - 75,000/mm3 (PMNs gt
  75)
• septic WBC gt 60,000/mm3 (PMNs gt80)
• GC may have WBC from 30K - 75K

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Synovial Fluid Analysis
Noninflammatory Type I Inflammatory Type II Septic Type III Hemorrhagic Type IV
Appearance Amber-yellow Yellow Purulent Bloody
Clarity Clear Cloudy Opaque Opaque
Viscosity High ( String sign) Decreased (- string) Decreased ( - string) Variable
Cell Count (PMN) 200-2000 (lt 25 PMN) 2000-75,000 ( gt 50 PMN) gt 60,000 ( gt80 PMN) RBC gtgt wbc
Examples OA Trauma Osteonecrosis SLE RA Reiters, gout SLE Tbc, fungal Bacterial Gout Trauma Fracture Ligament tear Charcot Jt. PVS