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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
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
The TEST
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Lectures: Big picture > stressed > anything covered
Syllabus: yes its dense with info. Look for overlap.
Lectures + Syllabus = synergistic importance
Common presentations, Common Disorders
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Common presentations of Uncommon Disorders
• Wont do Rare Presentations of Rare Disorders
Pathogenesis
Clinical manifestations & Outcome
Basic Treatment Decisions
6-8 Questions
Rheumatology Programme
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Tuesday 4/12
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Wednesday AM
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3rd Hr:
Gout, Pseudogout,
• Juvenile arthritis, Rheumatic Fever
4th Hr: Spondyloarthropathies: AS, Reactive, Psoriatic, IBD
Wednesday PM
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!st Hr: Evaluation of Rheumatic Patient
• Laboratory testing rheumatic pts
2nd Hr: SLE
• Osteoarthritis vs Rheumatoid arthritis
5th Hr: myositis, Scleroderma, Fibromyalgia, Carpal Tunnel
Thursday
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6th Hr: Vasculitis
• Infectious Arthritis, Lyme Disease
7th Hr: Anti-Rheumatic Drugs
• Test questions/review
Rheumatology
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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
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Whats the average age in rheumatology clinic?
70 million affected
 Only 3,200 Board Certified Rheumatologists in USA ()
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Rheumatologic Assessments
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What is needed to establish a differential diagnosis
Consider the most common conditions
Diagnosis by:
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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
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Age, Sex, Race
Type of presentation: Febrile, Acute, Chronic, Widespread pain
Number of Joints
in what OTHER diseases are they positive?
Arthrocentesis for diagnosis
Common Causes of Joint Pain
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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
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Goals of Assessment
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Identify “Red Flag” conditions
 Conditions
with sufficient morbidity/mortality to warrant an
expedited diagnosis
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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
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Provide relief, reassurance and plan for evaluation
and treatment
RED FLAG CONDITIONS
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FRACTURE
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SEPTIC ARTHRITIS
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GOUT/PSEUDOGOUT
Key Questions
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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,
Polymyalgia rheumatica
Osteoarthritis, Adhesive
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
Active+passive
in all planes
Active motion
in few planes
Common
Uncommon
ROM Pain
Swelling
Mono/Oligo vs Polyarticular
Monarticular
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Osteoarthritis
Fracture
Osteonecrosis
Gout or Pseudogout
Septic arthritis
Lyme disease
Reactive arthrtis
Tuberculous/Fungal arthritis
Sarcoidosis
Polyarticular
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Osteoarthritis
Rheumatoid arthritis
Psoriatic arthritis
Viral arthritis
Serum Sickness
Juvenile arthritis
SLE/PSS/MCTD
Nonarticular Pain
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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
Inflammatory
Noninflammatory
Articular
Nonarticular
Septic
Gout
Rheumatoid arthritis
Psoriatic arthritis
Osteoarthritis
Charcot Joint
Fracture
Bursitis
Enthesitis
PMR
Polymyositis
Fibromyalgia
Carpal tunnel
RSD
Musculoskeletal Complaint
Trauma
Fracture
Low Back
Pain?
Orthopedic Evaluation
Fibromyalgia
< 55 yrs.
> 55 yrs.
Repetitive Strain Injury
(carpal tunnel,bursitis)
Osteoarthritis
Gout
(males only)
Gout
Pseudogout
Rheumatoid
Arthritis
Polymyalgia
Rheumatica
Psoriatic
Reiters
IBD Arthritis
Osteoporotic
Fracture
Infectious
Arthritis
(GC, Viral,
Bacterial, Lyme)
Septic
Arthritis
(Bacterial)
History: Clues to Diagnosis
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Age
Young: JRA, SLE, Reiter's, GC arthritis
 Middle: Fibromyalgia, tendinitis, bursitis, LBP RA
 Elderly: OA, crystals, PMR, septic, osteoporosis
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Sex
Males: Gout, AS, Reiter's syndrome
 Females: Fibrositis, RA, SLE, osteoarthritis
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Race
White: PMR, GCA and Wegener's
 Black: SLE, sarcoidosis
 Asian: RA, SLE, Takayasu's arteritis, Behcet's
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Onset & Chronology
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Acute: Fracture, septic arthritis, gout, rheumatic fever,
Reiter's syndrome
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Chronic: OA, RA, SLE, psoriatic arthritis, fibromyalgia
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Intermittent: gout, pseudogout, Lyme, Familial
Mediterranean Fever
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Additive: OA, RA, psoriatic
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Migratory: Viral arthritis (hepatitis B), rheumatic fever,
GC arthritis
Drug – Induced Syndromes
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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
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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
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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
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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
TMJ
SC
AC
Shoulder
Elbow
Wrist
CMC1
MCP 1-5
PIP 1-5
Hip
Knee
Ankle
Tarsus
MTP 1-5
Toe 1-5
Left
 RHEUMATOSCREEN PLUS
 CBC & differential
 IgM- RF
 Lupus anticoag.
 Chem-20
 ANA
 Cardiolipin Ab
 Uric acid
 ENA (SSA, SSB,
 c-ANCA
 Urinalysis
 ESR
 C-reactive protein
 RPR
 CPK
 Aldolase
 ASO
 Immune complexs
 TFT’s w/ TSH
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RNP, Sm)
dsDNA-Crithidia
Scl-70, Jo-1
Histone Abs
Ribosomal P Ab
Coombs
C3, C4
CH50
Cryoglobulins
 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”
Kingstown General Hosp. CheapoScreen
CBC & diff
Chem-20
Urinalysis
ESR or CRP
Uric acid
$35.00
$108.00
$30.00
$25.30
$40.00
ANA
+
RF
$ 238.30
CUSHY LABS INC. “YOUR INDECISION IS OUR BREAD AND BUTTER”
Further Investigations
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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)
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Common Rheumatic Tests
Tests
Rheumatoid
Factor
Antinuclear
Antibody
Uric Acid
Sensitivity
Specificity
80%
95%
98%
93%
63%
96%
Acute Phase Reactants
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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
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ESR : Introduced by Fahraeus 1918
Mechanisms: Rouleaux formation
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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
ESR & Age
60
ESR mm/hr
50
40
30
20
10
0
<30 30-39 40-49 50-59 60-69 70-79 80-89
Age (years)
M=Age/2
F=Age+10/2
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)
42 (100)
37 (100)
Total
ACP Recommendations for Diagnostic Use of
Erythrocyte Sedimentation Rate
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The ESR should not be used to screen asymptomatic persons for disease
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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
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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
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The ESR is indicated for the diagnosis and monitoring of temporal arteritis and
polymyalgia rheumatica
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In diagnosing and monitoring patients with rheumatoid arthritis, the ESR should
be used prinicipally to resolve conflicting clinical evidence
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The ESR may be helpful in monitoring patients with treated Hodgkin’s disease
Antinuclear Antibodies
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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
Histones
Low titer=Nonspecific
Drug-induced lupus
Peripheral
ds-DNA
50% of SLE (specific)
Speckled
U1-RNP
Sm
Ro (SS-A)
>90% of MCTD
30% of SLE (specific)
Sjogrens 60%, SCLE
Neonatal LE, ANA(-)LE
50% Sjogrens, 15% SLE
40% of PSS (diffuse dz)
PM/DM
PM, Lung Dz, Arthritis
La (SS-B)
Scl-70
PM-1
Jo-1
Nucleolar
RNA Polymerase I, others
Centromere
Cytoplasmic
(nonspecific)
Kinetochore
Ro, ribosomal P
Cardiolipin
AMA, ASMA
40% of PSS
75% CREST (limited dz)
SS, SLE psychosis
Thrombosis,Sp. Abort, Plts
PBC, Chr. active hepatitis
Antinuclear Antibodies
 Virtually present in all SLE patients
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Not synonymous with a Dx of SLE
May be present in other conditions:
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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
Percent
ANA+ and Odds of SLE
100
90
80
70
60
50
40
30
20
10
0
1
2
3
criteria
4
+ANA
5
6
Frequency in SLE
Autoantibody
 dsDNA
 Sm
 RNP
 Ro
 Ribosomal P
 Histones
 ACA
Frequency
30-70%
20-40%
40-60%
10-15%
5-10%
30%
40-50%
Egner W, J Clin Pathol 53:424, 2000
Antiphospholipid Syndrome
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Triad: Any TEST plus:
 Thrombotic events
 Spontaneous abortion(s)
 Thrombocytopenia
Others: Migraine, Raynauds,
Libman-Sacks endocarditis, MR,
Transverse myelitis, neuropathy
Ab found in >30% SLE, other CTD
Correlates with IgG Ab and B2
Glycoprotein I
Rx: Warfarin, heparin
PTT/LAC
RPR
Cardiolipin
3 Tests
Rheumatoid Factor
Rheumatoid Factor
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80% of RA patients. High titers associated with greater disease
severity and extraarticular disease (NODULES).
Utility varies with use
Pre-test probability = 1%
 Pre-test probability = 50%
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Pos. Predictive Value =7%
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%
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20% of RA patients are seronegative for RF
Age and Serologic Testing
ANA
RF
16
14
percent (+)
12
10
8
6
4
2
0
20-30 yrs
> 65 yrs
Anti- Citrullinated Cyclic Peptides (CCP)
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RF+ only in 20-50% of Early RA patients
Antibodies against Filaggrin (AFA), Keratin (AKA), antiPerinuclear 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
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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 selfpeptides  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),
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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
Serum Urate mg/dl
Gout
5 year
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
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Class I MHC Ag, associated with the
spondyloarthropathies
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HLA-27 is found in up to 8% of normals
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Ankylosing spondylitis, Reiter's syndrome, Psoriatic
arthritis, and enteropathic arthritis.
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
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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
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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
Type I
Inflammatory
Type II
Septic
Type III
Hemorrhagic
Type IV
Amber-yellow
Yellow
Purulent
Bloody
Clear
Cloudy
Opaque
Opaque
Viscosity
High
(+ String sign)
Decreased
(- string)
Decreased
( - string)
Variable
Cell Count
(%PMN)
200-2000
(< 25% PMN)
2000-75,000
( > 50% PMN)
> 60,000
( >80% PMN)
RBC >> wbc
Examples
OA
Trauma
Osteonecrosis
SLE
RA
Reiters, gout
SLE
Tbc, fungal
Bacterial
Gout
Trauma
Fracture
Ligament tear
Charcot Jt.
PVS
Appearance
Clarity