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					                      John J. Cush, MD
              Chief, Rheumatology & Clinical Immunology
                     Presbyterian Hospital of Dallas
                Clinical Professor of Internal Medicine
                   UT Southwestern Medical School
St. John's University, B.S. 1977       Intern of the Year - Coney Island 1982
SGUSOM, MD July 1981                   Chief Medical Resident 1984
Internal Medicine Residency 81-84      Best Doctors In America 1996-2005
Chief Medical Resident 83-84           Teacher of the Year - PHD 1998-99
Rheumatology Fellowship                ”Best Doctors in Dallas” 2002-05
Parkland Memorial Hospital, 84 - 87    Arthritis Foundation, Chairman, Prof, Educ
                                       American College of Rheumatology
ECFMG, 1980; FLEX (I-III), 1981
                                       FDA Arthritis Advisory Committee 2002 -
License: GA, NY, TX 1989
                                       St. Georges University School of Medicine
Diplomate in Internal Medicine, 1984       Chairman, Academic Board 1990 -
Diplomate in Rheumatology, 1988            Trustee, Board of Trustee's 1993 –
UTSWMC Faculty 87- present             100 Publications
Chairman, Int Medicine SGU, 2004-      2 Books
                       The TEST
   Lectures: Big picture > stressed > 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
           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
                    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 ()
        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; H&P 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
      Common Causes of Joint Pain
   Musculoskeletal conditions > 70 million
        • 315 million MD office visits (Disability 17 million)
   Low Back Pain > 5 million per year
   Trauma/Fracture
   Osteoarthritis 12-20 million
   Repetitive strain/injury
      Bursitis,Tendinitis;Carpal 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
    Uncommon Causes of Joint Pain
 Systemic lupus erythematosus: 239,000
 Drug-induced lupus
 Scleroderma / CREST < 50,000
 Mixed Connective Tissue Disease (MCTD)
 Vasculitis (Polyarteritis nodosa, Wegeners granulomatosus)
 Inflammatory myositis <50,000
 Juvenile arthritis
 Behcets syndrome
 Sarcoidosis
 Relapsing polychrondritis
 Still’s Disease
              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
RED FLAG CONDITIONS

    FRACTURE
    SEPTIC ARTHRITIS
    GOUT/PSEUDOGOUT
                 Key Questions
   Inflammatory vs. Noninflammatory ?
   Acute vs. Chronic ? (< or > 6 weeks)
   Articular vs. Periarticular ?
   Mono/Oligoarthritis vs Polyarthritis ?
        (Focal)              (Widespread)

   Are there RED FLAGS?
       Inflammatory vs Noninflammatory
Feature                       Inflammatory                       Noninflammatory
Pain (worse when?)            Yes (morning)                      Yes (night)
Swelling                      Soft Tissue (+ effusion)           Bony
Erythema                      Sometimes Present                  Absent
Warmth                        Sometimes Present                  Absent
Morning Stiffness             Prominent ( > 1 hr.)               Minor ( < 45 min.)
Systemic Features+            Sometimes Present                  Absent
Elevated ESR or CRP*          Frequent                           Uncommon
Synovial Fluid WBC            WBC > 2,000 /mm3                   WBC < 2,000 /mm3
Examples                      Septic arthritis, RA, Gout,        Osteoarthritis, Adhesive
                              Polymyalgia rheumatica             Capsulitis,Osteonecrosis
+ fever, rash, weight loss, anorexia, anemia
* ESR: erythrocyte sedimentation rate; CRP: C-reactive protein
          Articular vs. Periarticular
Finding        ARTICULAR       PERIARTICULAR
Pain          Diffuse, deep    "point" tenderness


ROM Pain      Active+passive     Active motion
               in all planes     in few planes

Swelling        Common            Uncommon
     Mono/Oligo vs Polyarticular
Monarticular                       Polyarticular
   Osteoarthritis                    Osteoarthritis
   Fracture                          Rheumatoid arthritis
   Osteonecrosis
                                      Psoriatic arthritis
   Gout or Pseudogout
                                      Viral arthritis
   Septic arthritis
                                      Serum Sickness
   Lyme disease
   Reactive arthrtis                 Juvenile arthritis
   Tuberculous/Fungal arthritis      SLE/PSS/MCTD
   Sarcoidosis
                Nonarticular Pain
   Fibromyalgia
   Fracture
   Bursitis, Tendinitis, Enthesitis, Periostitis
   Carpal tunnel syndrome
   Polymyalgia rheumatica
   Sickle Cell Crisis
   Raynaud’s phenomenon
   Reflex sympathetic dystrophy
   Myxedema
     Formulating a Differential Dx
                      Articular          Nonarticular
Inflammatory            Septic               Bursitis
                         Gout              Enthesitis
                  Rheumatoid arthritis        PMR
                   Psoriatic arthritis    Polymyositis
Noninflammatory     Osteoarthritis        Fibromyalgia
                    Charcot Joint         Carpal tunnel
                      Fracture                RSD
Musculoskeletal Complaint
 Trauma                       Low Back
 Fracture                       Pain?

     Orthopedic Evaluation


                             Fibromyalgia
                < 55 yrs.                     > 55 yrs.
      Repetitive Strain Injury           Osteoarthritis
      (carpal tunnel,bursitis)


                Gout                           Gout
             (males only)                   Pseudogout


             Rheumatoid                     Polymyalgia
              Arthritis                     Rheumatica


               Psoriatic                 Osteoporotic
                Reiters                   Fracture
             IBD Arthritis


               Infectious                     Septic
                Arthritis                    Arthritis
              (GC, Viral,                   (Bacterial)
            Bacterial, Lyme)
          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
              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
       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
     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
     Rheumatic Review of Systems
   Fever/Constitutional: septic arthritis, vasculitis, Still’s 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
            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
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
         RHEUMATOSCREEN PLUS
 CBC & differential    IgM- RF              Lupus anticoag.
 Chem-20               ANA                  Cardiolipin Ab
 Uric acid             ENA (SSA, SSB,       c-ANCA
 Urinalysis
                           RNP, Sm)           anti-PR3, -MPO
                          dsDNA-Crithidia    anti-GBM
 ESR
                          Scl-70, Jo-1       SPEP
 C-reactive protein
                          Histone Abs        Lyme titer
 RPR
                          Ribosomal P Ab     HIV
 CPK
                          Coombs             Chlamydia Ab.
 Aldolase
                          C3, C4             Parvovirus B19
 ASO
                          CH50               HBV, HCV, HAV
 Immune complexs
                          Cryoglobulins      HLA typing
 TFT’s w/ TSH


CUSHY LABS INC. “YOUR INDECISION IS OUR BREAD AND BUTTER”
 Kingstown General Hosp. CheapoScreen


CBC & diff          $35.00
Chem-20             $108.00                 ANA
Urinalysis          $30.00                      +
ESR or CRP          $25.30
Uric acid           $40.00
                                              RF
                    $ 238.30


CUSHY LABS INC. “YOUR INDECISION IS OUR BREAD AND BUTTER”
             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 (<6wks)
     Chronicity ( > 6 weeks)
    Common Rheumatic Tests
Tests         Sensitivity   Specificity

Rheumatoid       80%           95%
 Factor
Antinuclear      98%           93%
 Antibody
Uric Acid        63%           96%
          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
       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
                                                           M=Age/2
                            ESR & Age                      F=Age+10/2
            60

            50

            40
ESR mm/hr




            30

            20

            10

            0
                 <30 30-39 40-49 50-59 60-69 70-79 80-89
                              Age (years)
 Extreme Elevation of ESR
            RME Fincher, Arch Int Med 146:1986

Cause               ESR > 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)
     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 Hodgkin’s disease
            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
ANA PATTERN     Ag Identified          Clinical Correlate
Diffuse         DeoxyRNP               Low titer=Nonspecific
                Histones                        Drug-induced lupus

Peripheral      ds-DNA                 50% of SLE (specific)

Speckled        U1-RNP                 >90% 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
(nonspecific)   Cardiolipin            Thrombosis,Sp. Abort, Plts
                AMA, ASMA              PBC, Chr. active hepatitis
                    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 > 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
                ANA+ and Odds of SLE
          100
           90
           80
           70
           60
Percent




           50
           40
           30
           20
           10
            0
                  1   2     3        4      5   6

                          criteria   +ANA
           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 53:424, 2000
      Antiphospholipid Syndrome
   Triad: Any TEST plus:
      Thrombotic events
      Spontaneous abortion(s)
                                            PTT/LAC
      Thrombocytopenia
   Others: Migraine, Raynauds,
    Libman-Sacks endocarditis, MR,
                                      RPR        Cardiolipin
    Transverse myelitis, neuropathy
   Ab found in >30% SLE, other CTD
   Correlates with IgG Ab and B2           3 Tests
    Glycoprotein I
   Rx: Warfarin, heparin
Rheumatoid Factor
                 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 >50% (Chaga’s, leishmaniasis, schistosomiasis), leprosy 35%,
       viral infection <50% (rubella, mumps, influenza-15-65%)
      Pulmonary Dz: Sarcoid <30%, IPF <50%, Silicosis 40%, Asbestosis 30%
      Malignancy 20%
      Primary Biliary Cirrhosis 50-75%

   20% of RA patients are seronegative for RF
               Age and Serologic Testing
                               ANA   RF
              16
              14
              12
percent (+)




              10
              8
              6
              4
              2
              0
                   20-30 yrs              > 65 yrs
    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
CCP antibodies by ELISA




  AITD: autoimmune thyroid dz; MGUS-monoclonal gammopathy; NC-normals
              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.
Serum Uric Acid & Incidence of Gout
                           Gout          5 year
 Serum Urate mg/dl
                     Incidence/yr/1000 cummulative

       < 7.0               0.8             5


     7.0 – 7.9             0.9             6

     8.0 – 8.9             4.1            9.8


       > 9.0               49             220
                         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
         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
             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 < 2000/mm3 (PMNs < 75%)
      inflammatory: WBC = 2000 - 75,000/mm3 (PMNs > 75%)
      septic: WBC > 60,000/mm3 (PMNs >80%)
         • GC may have WBC from 30K - 75K
                  Synovial Fluid Analysis
             Noninflammatory    Inflammatory      Septic        Hemorrhagic
                  Type I            Type II       Type III        Type IV
Appearance    Amber-yellow         Yellow         Purulent         Bloody

Clarity           Clear            Cloudy         Opaque          Opaque

Viscosity          High          Decreased       Decreased        Variable
              (+ String sign)     (- string)      ( - string)
Cell Count      200-2000         2000-75,000       > 60,000     RBC >> wbc
(%PMN)        (< 25% PMN)       ( > 50% PMN)    ( >80% PMN)
Examples           OA                RA           Bacterial        Trauma
                 Trauma         Reiters, gout      Gout            Fracture
              Osteonecrosis         SLE                         Ligament tear
                                                                 Charcot Jt.
                   SLE          Tbc, fungal
                                                                     PVS

				
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