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

Immune Mechanisms of Disease Type I: Anaphylactic IgE eg. asthma Type II: Cytotoxic eg. AIHA Type III: Immune Complex eg. SLE Type IV: Cell-mediated/Delayed Hypersensitivity: T-cells eg. Contact dermatitis

GENETICS ENVIRONMENT Infections... AUTOIMMUNITY

HLA: Disease Associations HLA B27 (MHC Class I) - Ankylosing Spondylitis - Reiter’s/reactive arthritis - Psoriatic arthritis - IBD arthropathy HLA DR4, DR1 (MHC Class II) - RA HLA DR3 (MHC Class II) - SLE, Sjogren’s, Type I DM…

We love our antibodies...

Rheumatoid Factor Rheumatoid Arthritis: - sensitivity = 70% Anti-antibodies (Fc domain of IgG) Rheumatoid Arthritis: - sensitivity = 70% - poor prognosis - extra-articular features Non-specific: - other rheumatic diseases eg. Sjogren’s - chronic inflammatory diseases - chronic infections – SBE, Hep C - 10-20% over age 65

Antinuclear Antibodies Sensitivity for SLE 90%+ Specificity low - other autoimmune diseases - family members - drugs - ...

Shmerling R. N Engl J Med 2003;349:1499-1500 Antinuclear Antibody (ANA) Test Results in a Hypothetical Population. Although the ANA may be present before the development of SLE, current estimates of disease incidence and test sensitivity and specificity suggest that most positive results are of uncertain (or no) clinical significance. Shmerling R. N Engl J Med 2003;349:1499-1500

Anti-centromere Antibodies: Limited Systemic Sclerosis (CREST)

Other Autoantibodies Anti-DNA (native, double-stranded) - SLE- sensitivity 60-70% - specificity ~ 100% - correlate with disease activity Anti-SSA, SSB (Ro, La) - Sjogren’s, SLE - congenital complete heart block

Anti-DNA (double stranded) Sensitivity for SLE: ~60% Specificity: ~ 100% Levels: may correlate with; - disease activity - hypocomplementemia - renal disease

Antibodies to Ro/SSA 30-35% of patients with Lupus Associated with: - Sjogren’s syndrome - photosensitive rashes “subacute cutaneous lupus” - Neonatal lupus - transient rashes - congenital complete heart block

Adult: Subacute Newborn: Cutaneous Lupus Neonatal Lupus Antibodies to Ro/SSA Adult: Subacute Newborn: Cutaneous Lupus Neonatal Lupus

Antiphospholipid Antibodies Anticardiolipin antibodies Lupus anticoagulant Associations: - thrombosis - recurrent pregnancy losses SLE, other CTD’s, primary

Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Patients with suspected vasculitis: - Wegener’s - pulmonary/renal - RPGN Cytoplasmic Perinuclear

Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Patients with suspected vasculitis - pulmonary/renal syndromes cANCA: Wegener’s Granulomatosus: - 80% sensitive and specific - specificity is for PR-3 pANCA: less specific

Wegener’s: cANCA (PR-3) Medium + small vessels Granulomatous Upper +/- lower respiratory Renal

Specific Diseases…

Osteoarthritis (OA) The most common type of arthritis Disease of cartilage (cf. RA) Characterized by: - Cartilage degradation, loss - hypertrophic bone formation (osteophytes...

Primary (idiopathic) OA Peripheral Joints: - hands - DIP, PIP (cf. RA) - 1st C-MC - feet - 1st MTP - large weight-bearing joints - hips, knees Spine - apophyseal joints - intervertebral discs

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

Osteoarthritis: X-ray 1st C-MC Joint Joint space narrowing Subchondral sclerosis Osteophytes

Rheumatoid Arthritis Prevalence 1:100 small joint, symmetric polyarthritis + AM stiffness chronic (>6weeks) Path = synovial inflammation Extra-articular features

DIPs  (spared) PIPs  MCPs 

Rheumatoid Arthritis Deformities Nodules Periarticular osteopenia Marginal erosions

RA: Extra-articular Features Skin - sc nodules, vasculitis... Eyes - sicca, scleritis, episcleritis Lungs - pleurisy/effusion - interstitial fibrosis - nodules Cardiac - pericarditis, nodules Hematologic - anemia, - Felty’s (neutropenia…) Neurologic - peripheral neuropathy...

Scleritis

RA: Nodules

RA: Factors Associated with Poor Prognosis Rheumatoid factor positivity HLA-DR4 haplotype Degree of disease activity at onset …  Early aggressive therapy

RA: Treatment Symptomatic - rest, education - splints, orthotics - ASA, NSAID’s, Coxibs Disease Modifying Anti-Rheumatic Drugs (DMARDs)

RA: Common DMARD’s Methotrexate Hydroxychloroquine Sulfasalazine New Biologics...

RA: New Therapies - Biologics anti-TNF soluble TNF receptor Concerns: - cost - parenteral - risk of infections, TB

Systemic Lupus Erythematosus Affects 1:1-2000 individuals African American blacks > Asian > Caucasian Females : Males = 9:1 Any age - usually young females in their reproductive years

Lupus: Criteria Malar rash Hematology: Photosensitivity anti-WBC Discoid rash Mucosal ulcers Arthritis Serositis “Pleurisy” Renal CNS Hematology: anti-WBC anti-platelet anti-rbc Immunologic: anti-DNA anti-phospholipid anti-Sm Antinuclear antibodies

SLE: Organs Affected Joints: 80-90% Skin: 70%, often photosensitive Serositis: 50% Kidneys: 25-50% CNS: 15%

Discoid Lupus Plaques Photosensitive Often head & neck Scarring 10% develop SLE

Lupus: Treatment Sunscreens, sunprotection Anti-inflammatory drugs Anti-malarial drugs Steroids Immunosuppressants Mycophenolate mofetil

Systemic Sclerosis (Scleroderma): Skin thickening, tightening

Scleroderma - small blood vessels = SPASM, ischemia + Disorder of: - small blood vessels = SPASM, ischemia + - overproduction of connective tissue (collagen) = FIBROSIS

Scleroderma: Types Systemic - Diffuse - Limited (CREST) - anti-centromere Localized - morphea - linear scleroderma

Raynaud’s phenomenon Cold, stress 3 phases: white blue  red 8-10% of normals 90% - scleroderma Consider ANA when screening (SLE, CREST)

Scleroderma Lungs - fibrosis - Pulmonary hypertension GI - GERD... Renal - malignant hypertension - microangiopathic anemia - renal failure - ACEI !!!!!!!!!!!!!!!!!!!

Limited Scleroderma (CREST) Calcinosis Telangiectasias

Acute Monoarthritis (in absence of trauma) Infection Crystal (gout, pseudogout) Spondyloarthropathy

Synovial Fluid Testing Cell count, differential WBC: 200-2000 = non-inflammatory 2000-100,000 = inflammatory >75,000 = septic Gram stain, C&S Crystals

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

Answer: Ankylosing Spondylitis

Spondyloarthropathies Axial and/or peripheral joints HLA-B27 Path = enthesopathy Inflammatory back pain Extra-articular: - uveitis etc. RF negative Ankylosing Spondylitis Reiter’s/reactive arthritis Psoriatic arthritis Inflammatory Bowel Disease

Enthesitis Erosion Calcaneal Spur Reiter’s - erosion at Achilles insertion into calcaneus and extra bone at site of plantar fasciitis Calcaneal Spur

Achilles tendinitis

Inflammatory low back pain? Insidious onset Worse with rest Better with activity Morning stiffness Family history Bilateral Sacroiliitis

HLA-B27: Disease Associations Ankylosing Spondylitis >90% Reiter’s syndrome/ reactive 80% Inflammatory bowel disease 50% Psoriatic Arthritis - with spondylitis 50% - with peripheral arthritis 15% Caucasians 8% Inuit 25%

Reactive Arthritis: Concept A sterile inflammatory arthritis - triggered by an infection - at a distant site (GI or GU) - in a genetically susceptible host An inflammatory reaction to a persistent organism or antigen(s)

Bacteria that Trigger Reactive Arthritis Post-venereal: Chlamydia trachomatis Post-dysenteric: Salmonella Shigella flexneri Yersinia enterocolitica Campylobacter Clostridium difficile

HLA-B27: Reactive Arthritis Campylobacter

Spondyloarthropathies: Extra-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 Syndrome

Gout Acute monoarthritis - lasts days - recurrent attacks Uncontrolled hyperuricemia  tophi  polyarthritis

Gout: uric acid crystals Needle-shaped Strong negative bireringence Phagocytosed by PMN’s

Gout: Treatment Asymptomatic hyperuricemia  none Acute attack - NSAID’s - colchicine - steroid’s Indications to lower uric acid - allopurinol - renal stones - frequent attacks - tophi

Pseudogout - CPPD Acute monoarthritis Knees, wrists Chondrocalcinosis Pyrophosphate crystals: - rhomboid - weak positive birefringence

Vasculitis: Classification Small Vessel Hypersensitivity Medium Vessel: - necrotizing = Polyarteritis nodosa - Kawasaki’s Large Vessel: - Giant Cell (Temporal) arteritis - Takayasu’s (Aortic Arch Syndrome)

Vasculitis: Classification NB! can have overlap... 1. Large Vessel Vasculitis 2. Medium Vessel Vasculitis 3. Small Vessel Vasculitis

Large Vessel Vasculitis - Giant Cell Arteritis - Takayasu’s (Aortic Arch Syndrome)

Medium Vessel Vasculitis - Polyarteritis nodosa (PAN) - Kawasaki Disease - Primary CNS Vasculitis

Small Vessel Vasculitis - ANCA Associated: - Wegener Granulomatosis - Churg-Strauss Syndrome - Microscopic Polyangiitis (MPA) - Henoch-Schönlein Purpura (HSP) - Vasculitis with connective tissue diseases - Vasculitis/essential mixed cryoglobulinemia (Hep C) - Hypersensitivity vasculitis (leukocytoclastic) - Vasculitis with viral infections (Hep B, C, HIV, CMV, parvo-B19)

Small Vessel Vasculitis Palpable purpura Most common vasculitis Leukocytoclastic vasculitis Ag (eg. Infection, drug) + Ab  immune complex Rule out other organ involvement (kidney, lung…)

Wegener’s Granulomatosis Small + medium vessels Granulomatous Upper +/- lower respiratory (ulcers, sinuses...) Renal

Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Patients with suspected vasculitis: Pulmonary - renal: - Wegener - ... Cytoplasmic Perinuclear

ANCA Immunofluorescence Solid Phase Assays (ELISA…) : cytoplasmic - cANCA perinuclear – pANCA Solid Phase Assays (ELISA…) : pANCA = anti-MPO (myeloperoxidase) cANCA = anti-PR3 (proteinase 3)

cANCA (anti-PR3) Highly sensitive, specific for Wegener’s granulomatosis Specificity: 95%

Giant Cell Arteritis (GCA) Age >50 years - mean = 70 years Symptoms related to arteries: - headache, scalp tenderness - visual loss - jaw claudication

Giant Cell (Temporal) Arteritis

Giant Cell (Temporal) Arteritis Diagnosis: - CBC - anemia of chronic disease - ESR - markedly elevated, often >100 - Biopsy temporal artery Treatment: URGENT! (prevent visual loss) - steroids - prednisone 60mg daily...

Fibromyalgia Tender Points (18)

Fibromyalgia Prevalence 3% widespread pain, tender points sleep disturbance Absence of inflammatory markers… Exclusion of other systemic disorders Treatment: - education - exercise - low dose tricyclic - New = pregabalin, duloxetine

NSAIDs, Coxibs

Toxicity: ASA and NSAIDs GI: ulcers, bleeding CVS: hypertension, increased risk MI, stroke Renal: Na retention, edema, renal failure CNS platelet effects contraindicated ASA hypersensitivity avoid if possible - pregnancy and lactation

Cox-2 “specific” Inhibitors (coxibs) improved GI safety no effect on platelets efficacious in RA, OA, pain ?? Increased risk MI, stroke renal effects like other NSAID’s  caution! - elderly - hypertension - cardiac disease - renal disease