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 NoninflammatoryFeatureInflammatoryNoninflammatoryPain (worse when?)Yes (morning)Yes (night)SwellingSoft Tissue (+ effusion)Bony ErythemaSometimes PresentAbsentWarmthSometimes PresentAbsentMorning StiffnessProminent ( > 1 hr.) Minor ( < 45 min.)Systemic Features+Sometimes PresentAbsentElevated ESR or CRP*FrequentUncommonSynovial Fluid WBCWBC > 2,000 /mm3WBC < 2,000 /mm3ExamplesSeptic arthritis, RA, Gout,Polymyalgia rheumaticaOsteoarthritis, AdhesiveCapsulitis,Osteonecrosis+ fever, rash, weight loss, anorexia, anemia * ESR: erythrocyte sedimentation rate; CRP: C-reactive protein

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

Musculoskeletal Complaint Initial Rheumatic History and Physical Exam to Determine:1. Is it articular2. Is it acute or chronic?3. Is inflammation present?4. How many/which joints are involved?

Is it Articular?

Is Complaint > 6 wks Duration?

Nonarticular Condition• Trauma/Fracture• Fibromyalgia• Polymyalgia Rheumatica• Bursitis• Tendinitis

ChronicAcuteAcute Arthritis

• Infectious Arthritis• Gout• Pseudogout• Reiter’s Syndrome

• Initial Presentation of Chronic Arthritis

Is Inflammation Present?1. Is there prolonged morning stiffness?2. Is there soft tissue swelling?3. Are there systemic symptoms?4. Is the ESR or CRP elevated?

Chronic Inflammatory Arthritis

Chronic Noninflammatory ArthritisHow Many Joints Involved?

Chronic InflammatoryMono/oligoarthritisConsider:• Indolent infection• Psoriatic Arthritis• Reiter’s Syndrome• Pauciarticular JA

Are DIP, CMC, Hip orKnee Involved?

Unlikely to be OsteoarthritisConsider:• Osteonecrosis• Charcot Arthritis

Osteoarthritis

Chronic InflammatoryPolyarthritis

Is it Symmetric?

Are PIP, MCP or MTPJoints Involved?

Consider:• SLE• Scleroderma• Polymyositis

Consider: • Psoriatic Arthritis• Reiter’s Syndrome

Rheumatoid Arthritis

Yes

No

Yes

Yes

No

No

No

Yes

Yes

NoNo Yes

1-3

>3

TraumaFracture

Orthopedic Evaluation

InfectiousArthritis

(GC, Viral,Bacterial, Lyme)

PsoriaticReiters

IBD Arthritis

RheumatoidArthritis

Gout(males only)

Repetitive Strain Injury(carpal tunnel,bursitis)

SepticArthritis

(Bacterial)

OsteoporoticFracture

PolymyalgiaRheumatica

GoutPseudogout

Osteoarthritis

Fibromyalgia

Low BackPain?

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, palindromic rheumatism, Behcet's, Familial Mediterranean Fever

Additive: OA, RA, Reiter's syndrome, psoriatic

Migratory: Viral arthritis (hepatitis B), rheumatic fever, GC arthritis, SLE

Arthralgias: Quinidine, amphotericin B, cimetadine, quinolones, chronic acyclovir, interferon, IL-2, nicardipine, vaccines

Myalgias/myopathy: Steroids, penicillamine, hydroxychloroquine, AZT, lovastatin, clofibrate, interferon, IL-2, alcohol, cocaine, taxol, colchicine, tryptophan

Gout: Diuretics, ASA, cytotoxics, cyclosporine, alcohol, moonshine, ethambutol

Drug-induced lupus: hydralazine, procainamide, quinidine, methyldopa, INH phenytoin, chlorpromazine, lithium, penicillamine, TCN, TNF inhibitors

Osteopenia: Steroids, chronic heparin, phenytoin, methotrexate Osteonecrosis: Steroids, alcohol, radiation therapy Scleroderma/tight skin: Vinyl chloride, bleomycin, pentazocine, solvents,

carbidopa, tryptophan, rapeseed oil Vasculitis: Allopurinol, amphetamines, cocaine, LSD, thiazide,

penicillamine, propylthiouracil

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

Acute Onset Arthritis 28 yr. old WF presents with acute onset of knee

swelling and pain 7 days ago. Two days later, knee resolved but both wrists began to swell. On day 7, the wrists improved but all PIPs were swollen and tender.

By day 10 she complained of arthritis in PIPs, wrists, knees and ankles. + Tenosynovitis L wrist. AM stiffness was 4 hours. C/O fatigue. Denies fever, rash

She visits her PCP who examines her and orders “Rheumatoscreen Plus” and XRAYs.

He sends her home on OTC ibuprofen, tylenol and Vicks Vapo-Rub.

Acute Onset Arthritis/Rash Day 14 she returns to PCP with

low grade fever, rash (pruritic) on the trunk and extremities.

Exam: symmetric polyarthritis in an RA-like distribution. Tenosynovitis has resolved. Urticarial lesions over trunk and extensor surface of arms. (+)2 cm nontender, left axillary LN. No malar rash, nodules, acne, or Raynauds phenomena.

Investigations?

Acute Onset Migratory Arthritis WBC = 11.2 H/H = 13.7 / 38.9 MCV = 89 ESR = 123 mm/hr SMA-12 WNL, except albumin = 3.3, AST-67, ALT 77 ANA negative RF 31 IU/ml (nl < 30 IU/ ml) C3 173, C4 28, ASO = 151 Todd units Uric Acid = 6.6 Normal SPEP, UPEP, TFT’s, TSH, Ferritin Others?

Acute Onset Arthritis/Rash She returns after 1 wk for LN Bx results (negative) Pt. states her rash and arthritis have nearly

resolved. Exam confirms only mild swelling in knees However, her sclera are definitely icteric. Next?

Migratory Arthritis Viral arthritis (hepatitis B)

Rheumatic fever

Gonococcal arthritis

SLE

Behcets

Hyperlipidemia

Hepatitis B Associated Arthritis

Arthritis and urticaria part of the “prodrome” Manifestations due to immune complex deposition Before the Jaundice Usually while LFTs elevated

Acute onset Additive (RA like) or migratory (ARF like) arthritis Often with tenosynovitis Synovial fluid: inflammatory Arthritis disappears with onset of Jaundice

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 Finkelsteins ext.pollicis brevisDeQuervains tenosynovitis 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”

Presbyterian 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

ESR mm/hr

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

Age (years)

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

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

Joint Pain and ANA+ 79 yoWM with schizophrenia and heart failure

presents with a 3 month hx of arthralgias affecting the knees, shoulders, elbows. His MD found +ANA 1:80

He complains of rashes, fever Says your stethoscope looks like a snake PMHx: as above, Meds: Lithium, Thorazine, aldomet, acromycin

VS: T=98.7 BP=110/75 R=18 P=88 Alert and oriented x 3 CVS exam: deferred Skin: Seborrheic dermatitis Joints: tender muscles and joints. No synovitis Labs: W 5.2, H/H 13/39, P178k, ESR 38, neg RF,

+ANA 1:80 speckled pattern Other tests? Diagnosis?

Joint Pain and ANA+

Reasons for +ANA

1. Age

2. Drugs (thorazine, lithium, aldomet, tetracycline)

3. Drug induced lupus???

4. No reason: ANA is low titer nonspecfic pattern

5. No evidence of SLE

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

0

1020

30

4050

6070

80

90100

1 2 3 4 5 6

Percent

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

ANA Associations Sensitivity (%)

Condition Lane Kavanaugh Drug-induced LE 100 SLE 99 95-100 Scleroderma 97 60-80 Sjogrens 96 40-70 MCTD 93 ~100 PM/DM 78 30-80 RA 40 30-50 Vasculitis 15 JRA 20-50 Raynauds 20-60

Lane SK, Gravel JW, Am Fam Phys 65:1073, 2002Kavanaugh AF, et al; Arch Pathol Lab Med 124: 71, 2000

Antiphospholipid Syndrome Triad

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

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

percent (+)

20-30 yrs > 65 yrs

ANA RF

CCP Antibodies(cyclic citrullinated peptide Abs)

Antibodies directed against Citrulline proteins AKA anti-filaggrin, anti-keratin and anti-perinuclear factor

antibodies (all identify filaggrin – citrulline rich) Citrulline is a post-translationally modified arginine residue that

binds “shared epitopes” (HLA-DR4 (HLADRB1 *0401, *0404) suggesting CCP Abs may play a role in RA pathogenesis .

Method: 2nd generation assay is widely available as EIA; has greater sensitivity than earlier version

Increased in: RA (sensitivity 50-70%); early RA (40-60%), RA with severe erosive disease. Specificity (95%) is higher than RF. CCP may be prognostically important in new onset RA

Indications: Suspected RA, new onset RA.

CCP antibodies by ELISA

AITD: autoimmune thyroid dz; MGUS-monoclonal gammopathy; NC-normals

Xray damage after 3 yrs in 178 RA patients assessed serologically

Van Jaarsveld CHM, et al. Clin Exp Rheumatol 17: 689, 1999Van Jaarsveld CHM, et al. Clin Exp Rheumatol 17: 689, 1999

Negative PPV: May be most important

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 GoutSerum Urate mg/dl Gout

Incidence/yr/1000

5 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

Knee Joint Injection

A Moran – Cush Video Exclusive

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

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