Rheumatology: Back to Basics: 2010 James Gillray “The Gout” “The Gout” 1799 1799.

Rheumatology: Rheumatology: Back to Basics: 2010Back to Basics: 2010

James James GillrayGillray

“ “The Gout”The Gout”

17991799

Immune Mechanisms of Immune Mechanisms of DiseaseDisease

Type I:Type I: Anaphylactic IgE eg. asthmaAnaphylactic IgE eg. asthma

Type II: Cytotoxic eg. AIHA Type II: Cytotoxic eg. AIHA

Type III: Immune Complex eg. SLEType III: Immune Complex eg. SLE

Type IV: Cell-mediated/Delayed Type IV: Cell-mediated/Delayed Hypersensitivity: T-cells Hypersensitivity: T-cells eg. Contact dermatitiseg. Contact dermatitis

GENETICSGENETICS ENVIRONMENTENVIRONMENT

AUTOIMMUNITAUTOIMMUNITYY

Infections.Infections.....

HLA: Disease AssociationsHLA: Disease Associations

HLA B27 (MHC Class I)HLA B27 (MHC Class I)

- Ankylosing Spondylitis- Ankylosing Spondylitis- Reiter’s/reactive arthritis- Reiter’s/reactive arthritis

- Psoriatic arthritis- Psoriatic arthritis- IBD arthropathy- IBD arthropathy

HLA DR4, DR1 (MHC Class II) HLA DR4, DR1 (MHC Class II) - RA- RA

HLA DR3 (MHC Class II)HLA DR3 (MHC Class II)

- SLE, Sjogren’s, Type I DM…- SLE, Sjogren’s, Type I DM…

We love our antibodies...We love our antibodies...

Rheumatoid FactorRheumatoid Factor

Anti-antibodiesAnti-antibodies (Fc domain of IgG) (Fc domain of IgG) Rheumatoid Arthritis:Rheumatoid Arthritis:

- sensitivity = 70% - sensitivity = 70% - poor prognosis- poor prognosis- extra-articular features- extra-articular features

Non-specific:Non-specific:- other rheumatic diseases eg. - other rheumatic diseases eg.

Sjogren’sSjogren’s- chronic inflammatory diseases- chronic inflammatory diseases- chronic infections – SBE, Hep C- chronic infections – SBE, Hep C- 10-20% over age 65- 10-20% over age 65

Antinuclear AntibodiesAntinuclear Antibodies

Sensitivity for SLE 90%+Sensitivity for SLE 90%+

Specificity lowSpecificity low

- other autoimmune diseases- other autoimmune diseases

- family members- family members

- drugs- drugs

- ...- ...

Shmerling R. N Engl J Med 2003;349:1499-1500

Anti-centromere Antibodies:Anti-centromere Antibodies:Limited Systemic Sclerosis Limited Systemic Sclerosis

(CREST)(CREST)

Other AutoantibodiesOther Autoantibodies

Anti-DNAAnti-DNA (native, double-stranded)(native, double-stranded)

- SLE- sensitivity 60-70%- SLE- sensitivity 60-70%

- specificity ~ 100%- specificity ~ 100%

- correlate with disease activity- correlate with disease activity

Anti-SSA, SSB (Ro, La)Anti-SSA, SSB (Ro, La)

- Sjogren’s, SLE- Sjogren’s, SLE

- congenital complete heart block- congenital complete heart block

Anti-DNA (double stranded)Anti-DNA (double stranded)

Sensitivity for SLE: Sensitivity for SLE: ~60%~60%

Specificity: Specificity: ~ 100%~ 100%

Levels: Levels: may correlate with;may correlate with;- disease activity- disease activity- hypocomplementemia- hypocomplementemia- renal disease- renal disease

Antibodies to Ro/SSAAntibodies to Ro/SSA

30-35% of patients with Lupus30-35% of patients with Lupus Associated with:Associated with:

- Sjogren’s syndrome- Sjogren’s syndrome

- photosensitive rashes “subacute - photosensitive rashes “subacute cutaneous lupus”cutaneous lupus”

- Neonatal lupus- Neonatal lupus

- transient rashes- transient rashes

- congenital complete heart - congenital complete heart blockblock

Antibodies to Ro/SSAAntibodies to Ro/SSA

Adult: Subacute Newborn:Cutaneous Lupus Neonatal Lupus

Antiphospholipid Antiphospholipid AntibodiesAntibodies

Anticardiolipin antibodiesAnticardiolipin antibodies Lupus anticoagulant Lupus anticoagulant

Associations:Associations:

- - thrombosisthrombosis

- recurrent pregnancy losses- recurrent pregnancy losses

SLE, other CTD’s, primarySLE, other CTD’s, primary

Anti-Neutrophil Cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies (ANCA)Antibodies (ANCA)

Patients with Patients with suspected suspected vasculitis:vasculitis:

- Wegener’s - Wegener’s

- pulmonary/renal- pulmonary/renal

- RPGN- RPGNCytoplasmic

Perinuclear

Anti-Neutrophil Anti-Neutrophil Cytoplasmic Antibodies Cytoplasmic Antibodies

(ANCA)(ANCA) Patients with suspected Patients with suspected vasculitis vasculitis

- pulmonary/renal syndromes- pulmonary/renal syndromes

cANCA: Wegener’s cANCA: Wegener’s Granulomatosus:Granulomatosus:

- 80% sensitive and specific - 80% sensitive and specific - specificity is for - specificity is for PR-3PR-3

pANCA: less specificpANCA: less specific

Wegener’s: cANCA (PR-3)

Medium + small Medium + small vesselsvessels

GranulomatousGranulomatous

Upper +/- lower Upper +/- lower respiratoryrespiratory

RenalRenal

Specific Diseases…Specific Diseases…

Osteoarthritis (OA)Osteoarthritis (OA)

The most common type of arthritisThe most common type of arthritis Disease of cartilage (cf. RA)Disease of cartilage (cf. RA) Characterized by:Characterized by:

- Cartilage degradation, loss- Cartilage degradation, loss

- hypertrophic bone formation- hypertrophic bone formation

(osteophytes...(osteophytes...

Primary (idiopathic) OAPrimary (idiopathic) OA

Peripheral Joints:Peripheral Joints:- hands- hands - DIP, PIP (cf. RA)- DIP, PIP (cf. RA)

- 1st C-MC- 1st C-MC- feet - 1st MTP- feet - 1st MTP- large weight-bearing joints - - large weight-bearing joints -

hips, kneeships, knees

SpineSpine - apophyseal joints- apophyseal joints- intervertebral discs- intervertebral discs

OA:OA: Heberden’s (DIP) Heberden’s (DIP) Bouchard’s (PIP) NodesBouchard’s (PIP) Nodes

Osteoarthritis: X-ray Osteoarthritis: X-ray 1st C-MC Joint1st C-MC Joint

Joint space Joint space narrowingnarrowing

Subchondral Subchondral sclerosissclerosis

OsteophytesOsteophytes

Rheumatoid ArthritisRheumatoid Arthritis

Prevalence 1:100Prevalence 1:100 small joint, symmetric polyarthritis small joint, symmetric polyarthritis

+ AM stiffness+ AM stiffness chronic (>6weeks)chronic (>6weeks) Path = synovial inflammation Path = synovial inflammation Extra-articular featuresExtra-articular features

DIPs DIPs

(spared)(spared)

PIPsPIPs

MCPsMCPs

Rheumatoid Rheumatoid ArthritisArthritis

DeformitiesDeformities NodulesNodules

Periarticular Periarticular osteopeniaosteopenia

Marginal Marginal erosionserosions

RA: Extra-articular RA: Extra-articular FeaturesFeatures

SkinSkin - sc nodules, vasculitis... - sc nodules, vasculitis... Eyes Eyes - sicca, scleritis, episcleritis- sicca, scleritis, episcleritis LungsLungs - pleurisy/effusion- pleurisy/effusion

- interstitial fibrosis- interstitial fibrosis

- nodules- nodules CardiacCardiac - pericarditis, nodules - pericarditis, nodules HematologicHematologic - anemia, - anemia,

- Felty’s (neutropenia…)- Felty’s (neutropenia…) NeurologicNeurologic - peripheral neuropathy... - peripheral neuropathy...

ScleritiScleritiss

RA: NodulesRA: Nodules

RA: Factors Associated with RA: Factors Associated with Poor PrognosisPoor Prognosis

Rheumatoid factor positivityRheumatoid factor positivity HLA-DR4 haplotypeHLA-DR4 haplotype Degree of disease activity at onsetDegree of disease activity at onset … …

Early aggressive therapyEarly aggressive therapy

RA: TreatmentRA: Treatment

SymptomaticSymptomatic

- rest, education- rest, education

- splints, orthotics- splints, orthotics

- ASA, NSAID’s, Coxibs- ASA, NSAID’s, Coxibs

Disease Modifying Anti-Rheumatic Disease Modifying Anti-Rheumatic Drugs (DMARDs)Drugs (DMARDs)

RA: Common DMARD’sRA: Common DMARD’s

MethotrexateMethotrexate HydroxychloroquineHydroxychloroquine SulfasalazineSulfasalazine New Biologics...New Biologics...

RA: New Therapies - RA: New Therapies - BiologicsBiologics

anti-TNF anti-TNF soluble TNF receptorsoluble TNF receptor Concerns:Concerns: - cost- cost

- parenteral- parenteral

- risk of infections, TB- risk of infections, TB

Systemic Lupus Systemic Lupus ErythematosusErythematosus

Affects 1:1-2000 individuals Affects 1:1-2000 individuals

African American blacks > Asian > African American blacks > Asian > CaucasianCaucasian

Females : Males = 9:1Females : Males = 9:1

Any age - usually young females in their Any age - usually young females in their reproductive yearsreproductive years

Lupus: CriteriaLupus: Criteria

1.1. Malar rashMalar rash

2.2. PhotosensitivityPhotosensitivity

3.3. Discoid rashDiscoid rash

4.4. Mucosal ulcersMucosal ulcers

5.5. ArthritisArthritis

6.6. Serositis Serositis “Pleurisy”“Pleurisy”

7.7. RenalRenal

8.8. CNSCNS

9.9. Hematology:Hematology:

anti-WBCanti-WBC

anti-plateletanti-platelet

anti-rbcanti-rbc

10.10. Immunologic:Immunologic:

anti-DNAanti-DNA

anti-phospholipidanti-phospholipid

anti-Smanti-Sm

11.11.Antinuclear antibodiesAntinuclear antibodies

SLE: Organs SLE: Organs AffectedAffected

Joints:Joints: 80-90% 80-90%

Skin:Skin: 70%, often 70%, often

photosensitivephotosensitive

Serositis:Serositis: 50% 50% Kidneys:Kidneys: 25-50% 25-50% CNS:CNS: 15% 15%

Discoid Lupus

PlaquesPlaques PhotosensitivePhotosensitive Often head & neckOften head & neck ScarringScarring 10% develop SLE10% develop SLE

Lupus: TreatmentLupus: Treatment

Sunscreens, sunprotectionSunscreens, sunprotection Anti-inflammatory drugsAnti-inflammatory drugs Anti-malarial drugsAnti-malarial drugs SteroidsSteroids ImmunosuppressantsImmunosuppressants Mycophenolate mofetilMycophenolate mofetil

Systemic Sclerosis Systemic Sclerosis (Scleroderma):(Scleroderma):

Skin thickening, tighteningSkin thickening, tightening

SclerodermaScleroderma

Disorder of:Disorder of:

- small blood vessels = SPASM, - small blood vessels = SPASM, ischemiaischemia

++

- overproduction of connective - overproduction of connective tissuetissue

(collagen) = FIBROSIS(collagen) = FIBROSIS

Scleroderma: TypesScleroderma: Types

SystemicSystemic - Diffuse- Diffuse- Limited (CREST)- Limited (CREST)

- anti-centromere- anti-centromere

LocalizedLocalized - morphea- morphea- linear - linear

sclerodermascleroderma

Raynaud’s phenomenonRaynaud’s phenomenon

Cold, stress 3 phases:Cold, stress 3 phases: white white blue blue red red

8-10% of normals8-10% of normals

90% - scleroderma90% - scleroderma

Consider ANA whenConsider ANA when screeningscreening (SLE, CREST)(SLE, CREST)

SclerodermaScleroderma

Lungs - fibrosis- Pulmonary hypertension

GI - GERD...

Renal - malignant hypertension- microangiopathic anemia

- renal failure

- ACEI !!!!!!!!!!!!!!!!!!!

Limited Scleroderma Limited Scleroderma (CREST)(CREST)

Calcinosis Telangiectasi

as

Acute Monoarthritis Acute Monoarthritis (in absence of trauma)(in absence of trauma)

InfectionInfection

Crystal (gout, Crystal (gout, pseudogout)pseudogout)

SpondyloarthropatSpondyloarthropathyhy

Synovial Fluid TestingSynovial Fluid Testing

Cell count, differentialCell count, differential

WBC: 200-2000 = non-inflammatoryWBC: 200-2000 = non-inflammatory

2000-100,000 = inflammatory2000-100,000 = inflammatory

>75,000 = septic>75,000 = septic

Gram stain, C&SGram stain, C&S

CrystalsCrystals

Question 1: What did Ramses II Question 1: What did Ramses II have, besides riches and fame?have, besides riches and fame?

Answer: Ankylosing Answer: Ankylosing SpondylitisSpondylitis

SpondyloarthropathiesSpondyloarthropathies

1.1. Ankylosing Ankylosing SpondylitisSpondylitis

2.2. Reiter’s/reactive Reiter’s/reactive arthritisarthritis

3.3. Psoriatic arthritisPsoriatic arthritis

4.4. Inflammatory Inflammatory Bowel DiseaseBowel Disease

Axial and/or Axial and/or peripheral jointsperipheral joints

HLA-B27HLA-B27 Path = enthesopathyPath = enthesopathy Inflammatory back Inflammatory back

painpain Extra-articular:Extra-articular:

- uveitis etc.- uveitis etc. RF negativeRF negative

Calcaneal Spur

Erosion

EnthesitisEnthesitis

Inflammatory low back Inflammatory low back pain?pain?

Insidious onsetInsidious onset Worse with restWorse with rest Better with Better with

activityactivity Morning Morning

stiffnessstiffness Family historyFamily history

Bilateral Sacroiliitis

HLA-B27: Disease HLA-B27: Disease AssociationsAssociations

Ankylosing SpondylitisAnkylosing Spondylitis >90%>90% Reiter’s syndrome/ reactiveReiter’s syndrome/ reactive 80%80% Inflammatory bowel disease Inflammatory bowel disease 50%50% Psoriatic Arthritis Psoriatic Arthritis

- with spondylitis - with spondylitis 50%50%

- with peripheral arthritis - with peripheral arthritis 15%15%

Caucasians Caucasians 8%8% InuitInuit 25%25%

Reactive Arthritis: Reactive Arthritis: ConceptConcept

A sterile inflammatory arthritis A sterile inflammatory arthritis - triggered by an infection- triggered by an infection - at a distant site (GI or GU) - at a distant site (GI or GU) - in a - in a genetically susceptible genetically susceptible

hosthost

An inflammatory reaction to a An inflammatory reaction to a persistent persistent organism or antigen(s)organism or antigen(s)

Bacteria that Trigger Bacteria that Trigger Reactive ArthritisReactive Arthritis

Post-venereal: Chlamydia Post-venereal: Chlamydia trachomatistrachomatis

Post-dysenteric:Post-dysenteric:

Salmonella Salmonella

Shigella flexneri Shigella flexneri

Yersinia enterocoliticaYersinia enterocolitica

CampylobacterCampylobacter

Clostridium difficileClostridium difficile

HLA-B27: Reactive ArthritisHLA-B27: Reactive Arthritis

CampylobacteCampylobacterr

Spondyloarthropathies: Spondyloarthropathies: Extra-articular featuresExtra-articular features

Skin: Psoriasis, E. nodosum, pyoderma gangrenosum...

Eyes: iritis, conjunctivitis Lungs: apical pulmonary fibrosis Cardiac: aortic insufficiency,

conduction abnormalities Neurologic: cauda equina...

Reiter’s SyndromeReiter’s Syndrome

GoutGout

Acute monoarthritisAcute monoarthritis

- lasts days- lasts days

- recurrent attacks- recurrent attacks

Uncontrolled Uncontrolled hyperuricemiahyperuricemia

tophitophi

polyarthritispolyarthritis

Gout: uric acid crystalsGout: uric acid crystals

Needle-shapedNeedle-shaped

Strong negative Strong negative bireringencebireringence

Phagocytosed by Phagocytosed by PMN’sPMN’s

Gout: TreatmentGout: Treatment

Asymptomatic hyperuricemia Asymptomatic hyperuricemia none none Acute attackAcute attack - NSAID’s- NSAID’s

- colchicine- colchicine

- steroid’s- steroid’s Indications to lower uric acid - allopurinolIndications to lower uric acid - allopurinol

- renal stones- renal stones

- frequent attacks- frequent attacks

- tophi - tophi

Pseudogout - CPPDPseudogout - CPPD

Acute monoarthritisAcute monoarthritis Knees, wristsKnees, wrists ChondrocalcinosisChondrocalcinosis

Pyrophosphate crystals:Pyrophosphate crystals:

- rhomboid- rhomboid

- weak positive - weak positive birefringencebirefringence

Vasculitis: ClassificationVasculitis: Classification

Small Vessel HypersensitivitySmall Vessel Hypersensitivity

Medium Vessel:Medium Vessel:- necrotizing = Polyarteritis nodosa- necrotizing = Polyarteritis nodosa- Kawasaki’s- Kawasaki’s

Large Vessel: Large Vessel: - Giant Cell (Temporal) arteritis- Giant Cell (Temporal) arteritis- Takayasu’s (Aortic Arch Syndrome)- Takayasu’s (Aortic Arch Syndrome)

Vasculitis: ClassificationVasculitis: ClassificationNB! can have overlap...NB! can have overlap...

1. Large Vessel Vasculitis1. Large Vessel Vasculitis

2. Medium Vessel Vasculitis2. Medium Vessel Vasculitis

3. Small Vessel Vasculitis3. Small Vessel Vasculitis

Large Vessel VasculitisLarge Vessel Vasculitis

- Giant Cell Arteritis- Giant Cell Arteritis

- Takayasu’s (Aortic Arch - Takayasu’s (Aortic Arch Syndrome)Syndrome)

Medium Vessel VasculitisMedium Vessel Vasculitis

- Polyarteritis nodosa (PAN)- Polyarteritis nodosa (PAN)

- Kawasaki Disease- Kawasaki Disease

- Primary CNS Vasculitis- Primary CNS Vasculitis

Small Vessel VasculitisSmall Vessel Vasculitis

- - ANCA Associated:ANCA Associated: - - Wegener GranulomatosisWegener Granulomatosis- Churg-Strauss Syndrome- Churg-Strauss Syndrome- Microscopic Polyangiitis - Microscopic Polyangiitis

(MPA)(MPA)

- Henoch-Schönlein Purpura - Henoch-Schönlein Purpura (HSP)(HSP)- Vasculitis with connective tissue diseases- Vasculitis with connective tissue diseases- Vasculitis/essential mixed cryoglobulinemia - Vasculitis/essential mixed cryoglobulinemia (Hep (Hep

C)C) - - Hypersensitivity vasculitis (leukocytoclastic)Hypersensitivity vasculitis (leukocytoclastic)- Vasculitis with viral infections (Hep B, C, HIV, CMV, - Vasculitis with viral infections (Hep B, C, HIV, CMV,

parvo-B19) parvo-B19)

Palpable purpuraPalpable purpura Most common vasculitisMost common vasculitis Leukocytoclastic Leukocytoclastic

vasculitisvasculitis Ag (eg. Infection, drug)Ag (eg. Infection, drug)

+ Ab + Ab immune complex immune complex Rule out other organ Rule out other organ

involvement (kidney, involvement (kidney, lung…)lung…)

Small Vessel Small Vessel VasculitisVasculitis

Wegener’s GranulomatosisWegener’s Granulomatosis

Small + medium Small + medium vesselsvessels

GranulomatousGranulomatous

Upper +/- lower Upper +/- lower respiratory respiratory (ulcers, (ulcers, sinuses...)sinuses...)

RenalRenal

Anti-Neutrophil Anti-Neutrophil Cytoplasmic Antibodies Cytoplasmic Antibodies

(ANCA)(ANCA)

Patients with Patients with suspected suspected vasculitis:vasculitis:

Pulmonary - Pulmonary - renal: renal:

- Wegener - Wegener

- ...- ...

Cytoplasmic

Perinuclear

ANCAANCA

ImmunofluorescenceImmunofluorescence• cytoplasmic - cANCAcytoplasmic - cANCA• perinuclear – pANCAperinuclear – pANCA

Solid Phase Assays (ELISA…) :Solid Phase Assays (ELISA…) :• pANCA = anti-MPO (myeloperoxidase)pANCA = anti-MPO (myeloperoxidase)• cANCA = anti-PR3cANCA = anti-PR3 (proteinase 3) (proteinase 3)

cANCA (anti-PR3)cANCA (anti-PR3)

Highly sensitive, specific for Highly sensitive, specific for Wegener’s granulomatosis Wegener’s granulomatosis

Specificity: 95%Specificity: 95%

Giant Cell Arteritis (GCA)Giant Cell Arteritis (GCA)

Age >50 years - mean = 70 Age >50 years - mean = 70 yearsyears

Symptoms related to arteries:Symptoms related to arteries:

- headache, scalp tenderness- headache, scalp tenderness

- visual loss- visual loss

- jaw claudication- jaw claudication

Giant Cell (Temporal) Giant Cell (Temporal) ArteritisArteritis

Giant Cell (Temporal) Giant Cell (Temporal) ArteritisArteritis

Diagnosis:Diagnosis:

- CBC - anemia of chronic disease- CBC - anemia of chronic disease

- ESR - markedly elevated, often >100- ESR - markedly elevated, often >100

- Biopsy temporal artery- Biopsy temporal artery

Treatment: Treatment: URGENT! (prevent visual URGENT! (prevent visual loss)loss)

- steroids - prednisone 60mg daily...- steroids - prednisone 60mg daily...

Fibromyalgia Tender Points (18)

FibromyalgiaFibromyalgia

Prevalence 3%Prevalence 3% widespread pain, tender pointswidespread pain, tender points sleep disturbancesleep disturbance Absence Absence of inflammatory markers…of inflammatory markers… Exclusion Exclusion of other systemic disordersof other systemic disorders Treatment:Treatment: - education- education

- exercise- exercise- low dose tricyclic- low dose tricyclic- New = pregabalin, - New = pregabalin,

duloxetineduloxetine

NSAIDs, CoxibsNSAIDs, Coxibs

Toxicity: ASA and NSAIDsToxicity: ASA and NSAIDs

GI: ulcers, bleedingGI: ulcers, bleeding CVS: hypertension, increased risk MI, CVS: hypertension, increased risk MI,

strokestroke Renal: Na retention, edema, renal failureRenal: Na retention, edema, renal failure CNSCNS platelet effectsplatelet effects contraindicated ASA hypersensitivitycontraindicated ASA hypersensitivity avoid if possible - pregnancy and avoid if possible - pregnancy and

lactation lactation

Cox-2 “specific” Inhibitors Cox-2 “specific” Inhibitors (coxibs)(coxibs)

improved GI safetyimproved GI safety no effect on plateletsno effect on platelets efficacious in RA, OA, painefficacious in RA, OA, pain

X ?? Increased risk MI, stroke?? Increased risk MI, strokeX renal effects like other NSAID’srenal effects like other NSAID’s

caution!caution! - elderly - elderly - hypertension- hypertension- cardiac disease- cardiac disease- renal disease- renal disease