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RHEUMATIC DISEASE LABORATORY TESTING

RHEUMATIC DISEASE LABORATORY TESTING. Pitfalls: Misdiagnosis Permanent labeling of patient Needless additional testing Inappropriate therapy and/or referral Expense Overlooking the correct diagnosis NEEDLESS ANXIETY FOR PATIENT!!!. Intent: Establish a diagnosis Determine prognosis

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RHEUMATIC DISEASE LABORATORY TESTING

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  1. RHEUMATIC DISEASE LABORATORY TESTING

  2. Pitfalls: Misdiagnosis Permanent labeling of patient Needless additional testing Inappropriate therapy and/or referral Expense Overlooking the correct diagnosis NEEDLESS ANXIETY FOR PATIENT!!! Intent: Establish a diagnosis Determine prognosis Monitor disease activity Indicate organ involvement Monitor stage of disease Indicate disease mechanisms Guide treatment Monitor toxicity BASICS OF LAB TEST ORDERING

  3. BASICS OF LAB TEST ORDERING “We checked an ANA, ESR, & RF to look for connective tissue disease…..”

  4. TWO BY TWO TABLE

  5. DISEASE PREVALENCE & PREDICTIVE VALUES

  6. SNOUT A test with high SeNsitivity is excellent For ruling OUT a dx… “SNOUT” Sensitivity is true pos over true pos plus false negatives

  7. SPIN A test with a high SPecificity is great for Ruling IN a dx “SPIN” Specificity is true negative over true negative plus false positive

  8. TYPES OF LABS 1. High sensitivity labs - SNOUT: • good for “screening” or “ruling out” • ESR (inflammation) • ANA (lupus – but NOT “CTD”) 2. High specificity labs - SPIN: • good for “diagnosing” or “ruling in” • ds-DNA (lupus) • Scl-70 (PSS) • Jo-1 (ILD in polymyositis) • C-ANCA (WG)

  9. TYPES OF LABS 3. Disease activity labs: • How is treatment working ? • CPK • complement levels (lupus) • ds-DNA (lupus) • ESR, CRP (RA, GCA, PMR) 4. Prognosis labs: • Should I be aggressive early with meds? • RF (RA) • ds-DNA antibody (SLE) • Citrulline antibody (RA)

  10. “THE NET” – looking for organ damage and mimickers • UA with micro • glomerulonephritis • CBC • anemia chronic disease • Lipids • accelerated atherogenesis w/ inflammation • Hep B & Hep C • extrahepatic disease features. • TSH • CPK • Chem Panel and LFT’s • ? Vitamin D (fibromyalgia)

  11. ESR

  12. ESR • The king of non-specific lab tests but very sensitive • Infection / malignancy/CTD all raise the ESR • Westergren method used at NMCSD (up to 120 mm/hr) • Useful for “ruling out” systemic inflammatory disease

  13. ESR • Non-inflammatory factors that raise ESR • Aging • Female Sex • Obesity • Pregnancy • Anemia • Markedly Low ESR (0 mm/hr) • Afribinogenemia/dysfibrinogenemia • Agammaglobulinemia • Extreme polycythemia (HCT > 65) • Increased plasma viscosity

  14. ESR • Adjunctive Testing • Good history and physical • Repeat test 1-3 mo? Prior ESRs? • CRP • SPEP, Quantitative Immune Globulins • Age Appropriate Malignancy Screen

  15. CRP (“Can’t refuse prednisone”) • Produced as an acute-phase reactant by the liver in response to IL-6 and other cytokines • Seen in sera of patients with pneumococcal pneumonia in 1930 (protein could precipitate C-polysaccharide of pneumococcus) • Can recognize phosphocholine, other phospholipids • Can activate complement (classic) • Can bind to and modulate the behavior of phagocytic cells in both pro and anti-inflammatory ways • Quicker rise and fall than ESR • Sensitive but not diagnostic of any particular condition • “CRP rises with infection and ESR rises with CTD’s….” (not always true!!!) • Normal less than 1.0 mg/dl • > 8-10 mg/dl, think bacterial infection, systemic vasculitis, or widely metastatic cancer

  16. CRP

  17. OTHER ACUTE PHASE REACTANTS • Polyclonal Immunglobulins (SPEP) • Alkaline phosphatase • Transaminases • Fibrinogen • Haptoglobin • Serum amyloid A • Platelet count • Ferritin • Alpha-1 antitrypsin • Decreased albumin (“negative” APR)

  18. COMPLEMENT • A system of interacting serum proteins that function sequentially as initiators, regulators, and effectors of cell lysis and inflammation • Provide innate defense against microbes and a “complement” to humoral immunity • Biologic cascade in which, by limited proteolysis, one component activates the next, causing rapid and robust amplification of the system • Critical to normal processing of immune complexes • Causes host tissue damage in antibody-mediated autoimmune syndromes

  19. COMPLEMENT • Measurement useful if: • concern for inherited deficiency states which can pre-dispose to infectious and rheumatic syndromes • immune-complex mediated disease

  20. COMPLEMENT

  21. COMPLEMENT CLASSICAL: Ag-Ab complexes such as SLE ALTERNATIVE: Endotoxin IgA Drugs

  22. COMPLEMENT

  23. COMPLEMENT REGULATION • C1 inhibitor – [prevents C1s from activating C4 and C2] • deficiency -> hereditary angioneurotic edema and chronic C4 activation/consumption with resulting low C4 • C3 and C4 nephritic factors • Autoantibodies against alternative and classical pathway C3 convertases, respectively • Stabilizes antibody, increasing half-life causing excessive C3 cleavage • Secondary deficiency of C3

  24. ROUTINE COMPLEMENT LEVEL TESTING • CH 50 • reflects a functionally intact classic pathway; good screen for deficiency state (C1-9) • C3 • useful screen for BOTH classic and alternative pathways • C4 • depressed with activation of classic pathway or in patients with angioneurotic edema • C5-9 • terminal attack complex

  25. DIMINISHED COMPLEMENT LEVELS • partial or complete inherited deficiency • C1q inhibitor deficiency -> hereditary angioedema and low C4 • C2 or C4 deficiency -> SLE • C3 deficiency -> recurrent infections (bacterial) • C5a inhibitor deficiency -> FMF • C5-9 deficiency -> recurrent neisserial infxn • immune complex consumption • (SLE / post-strep GN, cryoglobulinemia, SBE, membranoproliferative GN, Sjogren’s, other vasculitides)

  26. RHEUMATOID FACTOR

  27. Hemagglutinating activity noted in 1940, associated with RA in 1949 Heterogeneous family of IgM abys directed against IgG RF response transiently associated with many infectious diseases (TB, SBE, syphillis, HCV) RF response more permanent with chronic diseases 1-4% of healthy whites, 10-25% age > 70 , 30% some NA Indians 80% of RA pts (+) 80-90% of SS (+) 70% of chronic HCV (+) Both Types II and III cryoglobulins worse prognosis and more aggressive RA Not specific for RA No correlation with RA disease activity RHEUMATOID FACTOR

  28. RHEUMATOID FACTOR

  29. RHEUMATOID FACTOR

  30. Elevated RF (ChRONIC immune stimulation) • Ch- chronic disease (esp hepatic and pulmonary) • R- rheumatoid arthritis • O- other connective tissue disease • N- neoplasms (lymphoproliferative diseases, esp after XRT, chemo) • I – Infections • C - cyroglobulins

  31. ANTI-CITRULLINE AB • ELISA available against CCP (cyclic citrullinated peptide) – one of the anti-filaggrin antibodies • Very specific, not very sensitive (SPIN) • Utility may be in defining early and aggressive RA, prior to development of RF • Useful in RF (+) positive conditions that mimic RA • Sjogren’s • Hep C • cryoglobulinemia

  32. ANA • ANA’s are directed against a variety of nuclear antigens in serum of patients with/without rheumatic disease as well as in normal persons • The ANA IS NOT a useful screen for rheumatic disease (nor is the RF) • not sensitive enough (SNOUT) • not specific enough (SPIN) • The ANA IS a useful screen for SLE • is very sensitive-95% (SNOUT) • Offers less in area of specificity (SPIN)

  33. ANA • many false positives • 5% of healthy controls pos at 1:160 dilution • 10-15% of healthy controls pos at 1:80 dilution • 30% of healthy controls pos at 1:40 dilution • positive with SBE / age / liver disease / thyroid dz • should be done on HEp2 cell line • pattern is important and helps w/ dx • titer doesn’t correlate with disease activity • a negative ANA “rules out” SLE most of the time

  34. ANA TESTING

  35. ANA PATTERNS RIM HOMOGENEOUS NUCLEOLAR SPECKLED

  36. NUCLEOLAR Against RNA Nonspecific Associated with PSS PM-DM SLE vasculitis RIM or PERIPHERAL Against DNA Specific for SLE Should trigger check for ds-DNA SLE More active disease Nephritis ANA PATTERNS

  37. ANA PATTERNS CENTROMERE • Associated with CREST • Calcinosis • Raynaud’s • Esophageal Dysmotility • Sclerodactyly • Telangeictases

  38. HOMOGENEOUS Against DNA & histone Nonspecific Associated with SLE Drug induced lupus RA Vasculitis PM-DM SPECKLED Against the various ENA’s “More” specific-SPIN Associated with SLE Sjogren’s PSS PM-DM RA ANA PATTERNS

  39. SPECIFIC ANA’s ds-DNA • Nearly 100% specific for SLE • Correlates well with disease activity • Probably pathogenic • Moderate Sensitivity

  40. SPECIFIC ANA’s Smith (Sm) • RNA/protein complex involved in processing messenger RNA • More severe disease • Speckled ANA • Higher prevalence in AA & Asians • Moderate sensitivity (30%) • Highly specific for SLE

  41. RNP (U1 RNP) Ribonucleoprotein Speckled ANA Diagnostic of MCTD if: High titer No other ENA’s Features of SLE, PM, RA, and PSS RF (+) HISTONE High sensitivity and low specificity Drug induced lupus gives anti-histone alone SLE gives anti-histone along with ds-DNA Also seen in RA SPECIFIC ANA’s

  42. Ro/SS-A Protein-RNA complex found in both nucleus and cytoplasm Sjogren’s and lupus The rare ANA-neg lupus Subacute cutaneous lupus (a very photosensitive lupus) Neonatal SLE and congenital heart block La/SS-B Protein-RNA complex found in both nucleus and cytoplasm Sjogren’s and lupus The rare ANA-neg lupus May protect against renal disease Usually also have antibodies to Ro/SS-A SPECIFIC ANA’s

  43. Ro/SS-A & La/SS-B

  44. SCL-70 Anti-topoisomerase I Found in 20% of patients with PSS VERY specific NOT sensitive Lung disease Associated with nucleolar ANA pattern Jo-1 Anti-histidyl tRNA synthetase A cytoplasmic protein Found in 30% of PM/DM patients – often with lung involvement/ILD Highly specific SPECIFIC ANA’s

  45. CRYOGLOBULINS

  46. A group of serum Ig’s with conformational change in the cold: Precipitate or gel on cold exposure Phenomenon reversible with rewarming Found in variety of clinical situations Other labs: RF, low complement, QIG, ESR TYPE I Single monoclonal Ig or light chain TYPE II (essential) “mixed” – a monoclonal directed against polyclonal IgG (rheumatoid factor activity) TYPE III “polyclonal” – no monoclonal Ig also RF activity CRYOGLOBULINS

  47. CRYOGLOBULINS • Type I (myeloproliferative disorders) • Myeloma, lymphoma, Waldenstrom’s • Type II • Infections (majority HCV and some HBV), CTD (Sjogren’s, lupus), • Type III • CTD, Infection • lymphoproliferative disorder

  48. CRYOGLOBULINS • “Essential mixed cryoglobulinemia” is now recognized as driven by chronic Hep C in most cases. • Clinical features: • Acrocyanosis / digital necrosis (type I) • Palpable purpura (type II and III) • Livedo reticularis • Raynaud’s • Arthritis / GN / peripheral neuropathies

  49. HLA B-27 • Class I MHC cell surface marker • found in 6-8% of NA whites, 3-4% of NA AA’s, 18-50% of Haida Indians • 90-100% of AS pts/lesser frequency in other spondyloarthropathies • NOT a “screening” test for the SNSA’s • IBD-associated arthritis – 50% • Ankylosing spondylitis (AS) – 90% • Reactive / Reiter’s – 80% • Psoriatic arthritis – 50% w/ spine; 15% peripheral

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