John J. Cush, MDChief, Rheumatology & Clinical Immunology

Presbyterian Hospital of DallasClinical Professor of Internal Medicine

UT Southwestern Medical SchoolSt. John's University, B.S. 1977SGUSOM, MD July 1981Internal Medicine Residency 81-84Chief Medical Resident 83-84Rheumatology FellowshipParkland Memorial Hospital, 84 - 87ECFMG, 1980; FLEX (I-III), 1981License: GA, NY, TX 1989Diplomate in Internal Medicine, 1984Diplomate in Rheumatology, 1988UTSWMC Faculty 87- presentChairman, Int Medicine SGU, 2004-

Intern of the Year - Coney Island 1982Chief Medical Resident 1984Best Doctors In America 1996-2005Teacher of the Year - PHD 1998-99”Best Doctors in Dallas” 2002-05Arthritis Foundation, Chairman, Prof, EducAmerican College of RheumatologyFDA Arthritis Advisory Committee 2002 - St. Georges University School of Medicine Chairman, Academic Board 1990 - Trustee, Board of Trustee's 1993 – 100 Publications2 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

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

Uncommon Causes of Joint PainUncommon Causes of Joint Pain

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 NoninflammatoryFeature 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, AdhesiveCapsulitis,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 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

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 NonarticularInflammatory Septic

Gout

Rheumatoid arthritis

Psoriatic arthritis

Bursitis

Enthesitis

PMR

Polymyositis

Noninflammatory Osteoarthritis

Charcot Joint

Fracture

Fibromyalgia

Carpal tunnel

RSD

Traum aFrac ture

O rthopedic E valuation

Infec tiousA rthritis

(G C , V ira l,B acteria l, Lym e)

P soria ticR eiters

IB D A rthritis

R heum ato idA rthritis

G out(m ales only)

R epetitive S tra in In jury(carpal tunnel,burs itis)

S epticA rthritis

(B ac teria l)

O s teoporoticF rac ture

P olym yalg iaR heum atica

G outP seudogout

O s teoarthritis

F ibrom yalg ia

Low B ackP ain?

Musculoskeletal Complaint

< 55 yrs. > 55 yrs.

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

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

Drug – Induced Syndromes

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 TearTrauma? 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 Chem-20 Uric acid Urinalysis ESR C-reactive protein RPR CPK Aldolase ASO Immune complexs TFT’s 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”

ANA+

RF

CBC & diff $35.00

Chem-20 $108.00

Urinalysis $30.00

ESR or CRP $25.30

Uric acid $40.00

$ 238.30

CUSHY LABS INC. “YOUR INDECISION IS OUR BREAD AND BUTTER”

Kingstown General Hosp. CheapoScreen

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

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

Erythrocyte Sedimentation Rate

ESR & Age

0

10

20

30

40

50

60

ES

R m

m/h

r

<30 30-39 40-49 50-59 60-69 70-79 80-89

Age (years)

M=Age/2F=Age+10/2

Extreme Elevation of ESRRME 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 MCTDSm 30% of SLE (specific)Ro (SS-A) Sjogrens 60%, SCLE

Neonatal LE, ANA(-)LELa (SS-B) 50% Sjogrens, 15% SLEScl-70 40% of PSS (diffuse dz)PM-1 PM/DMJo-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

01020

3040506070

8090

100

1 2 3 4 5 6

Per

cent

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) 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 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

0

2

4

6

8

10

12

14

16

perc

ent

(+)

20-30 yrs > 65 yrs

ANA RF

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

Serum Urate mg/dlGout

Incidence/yr/10005 year

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

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

(< 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

TraumaFracture

Ligament tearCharcot Jt.

PVS

Synovial Fluid Analysis