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Rheumatologic Assessments What is needed to establish a differential diagnosis Consider the most common conditions Diagnosis by: 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 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 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 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 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 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 Inflammatory Noninflammatory Articular Nonarticular Septic Gout Rheumatoid arthritis Psoriatic arthritis Osteoarthritis Charcot Joint Fracture Bursitis Enthesitis PMR Polymyositis Fibromyalgia Carpal tunnel RSD Musculoskeletal Complaint Initial Rheumatic History and Physical Exam to Determine: 1. 2. 3. 4. Nonarticular Condition • • • • • Trauma/Fracture Fibromyalgia Polymyalgia Rheumatica Bursitis Tendinitis Is it articular Is it acute or chronic? Is inflammation present? How many/which joints are involved? Is it Articular? No Yes Is Complaint > 6 wks Duration? No Acute Arthritis • • • • Infectious Arthritis Gout Pseudogout Reiter’s Syndrome Yes Acute Chronic • Initial Presentation of Chronic Arthritis Is Inflammation Present? 1. 2. 3. 4. Is there prolonged morning stiffness? Is there soft tissue swelling? Are there systemic symptoms? Is the ESR or CRP elevated? No Yes Chronic Inflammatory Arthritis Chronic Noninflammatory Arthritis Are DIP, CMC, Hip or Knee Involved? No Yes Chronic Inflammatory Mono/oligoarthritis Consider: • • • • 1-3 How Many Joints Involved? Indolent infection Psoriatic Arthritis Reiter’s Syndrome Pauciarticular JA >3 Chronic Inflammatory Polyarthritis No Consider: Unlikely to be Osteoarthritis Consider: • Osteonecrosis • Charcot Arthritis Osteoarthritis • Psoriatic Arthritis • Reiter’s Syndrome Consider: • SLE • Scleroderma • Polymyositis No Is it Symmetric? Yes Are PIP, MCP or MTP Joints Involved? Yes Rheumatoid Arthritis 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 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 Drug – Induced Syndromes 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 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 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 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” Presbyterian 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 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 Rheumatoid Factor Antinuclear Antibody Uric Acid Sensitivity Specificity 80% 95% 98% 93% 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 Erythrocyte Sedimentation Rate 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 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 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 Joint Pain and ANA+ 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? Reasons for +ANA 1. 2. 3. 4. 5. Age Drugs (thorazine, lithium, aldomet, tetracycline) Drug induced lupus??? No reason: ANA is low titer nonspecfic pattern 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 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 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 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 ANA Associations Condition Drug-induced LE SLE Scleroderma Sjogrens MCTD PM/DM RA Vasculitis JRA Raynauds Sensitivity (%) Lane Kavanaugh 100 99 97 96 93 78 40 15 Lane SK, Gravel JW, Am Fam Phys 65:1073, 2002 Kavanaugh AF, et al; Arch Pathol Lab Med 124: 71, 2000 95-100 60-80 40-70 ~100 30-80 30-50 20-50 20-60 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% Pre-test probability = 50% 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% 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 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 Negative PPV: May be most important Van Jaarsveld CHM, et al. Clin Exp Rheumatol 17: 689, 1999 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/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 HLA-27 is found in up to 8% of normals 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 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 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