CLM Rheumatology

RHEUMATOLOGY

Overview

  • Rheumatology: the study of a multitude of disorders characterized by inflammation, often due to disordered immunity including autoimmune conditions.

OBJECTIVES

  • Understand the physiology, implementation, and interpretation of laboratory tests in Rheumatology and Toxicology as relevant to patient-specific pathology.

  • Identify common rheumatologic conditions and their laboratory findings.

  • Review the indications for obtaining tests such as ANA, C-ANCA, P-ANCA and examine their diagnostic utility.

  • Accurately order, interpret, and summarize various autoimmune markers and tests associated with specific disease states, e.g., Anti-dsDNA, Anti-Smith, HLA-B27, RF, Anti-CCP.

  • Understand and order ESR and CRP when evaluating rheumatologic disease.

  • Apply basic pharmacokinetic principles to therapeutic drug monitoring.

  • Identify common drugs of abuse and their testing methods.

  • Order appropriate tests and summarize results for common environmental toxins.

RHEUMATOLOGY LABORATORY TESTING

General Approach

  • Complete Blood Count (CBC): Monitoring for WBC changes and evaluating anemia linked to autoimmune disease.

  • Urinalysis: Observing for protein or blood to indicate kidney dysfunction.

  • Creatine Phosphokinase (CPK/CK): Indicates muscle damage, potentially suggesting myositis.

  • Erythrocyte Sedimentation Rate (ESR): A sign of autoimmune disease or chronic inflammation through RBC rouleaux formation.

  • C-Reactive Protein (CRP): Acute phase reactant indicating inflammation.

  • Comprehensive Metabolic Panel (CMP): Evaluating organ damage or dysfunction.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Characteristics

  • Chronic inflammatory autoimmune condition.

  • Affects women disproportionately (9:1 compared to men).

  • Increased risk among different ethnic groups: Black > Latino > Asian > Caucasian.

  • Prevalence can be as high as 51 per 100,000 in the US.

Symptoms

  • Variable presentation including:

    • Fatigue

    • Fever

    • Malar rash (butterfly rash)

    • Arthralgia (90% experience arthritis)

    • Alopecia

    • Mouth ulcers

    • Generalized adenopathy (sparing nasolabial folds)

Laboratory Testing

  • Recommended tests:

    • CBC: Can show anemia.

    • CMP: Evaluate organ function.

    • Urinalysis: Look for RBC/WBC casts suggesting active nephritis and proteinuria (measured by urine protein/creatinine ratio or 24-hour urine collections).

    • ANA: High titer (>1:80).

    • Anti-dsDNA: Positive in approximately 50% of cases.

    • Anti-Smith: Positive in about 20% of cases.

RHEUMATOLOGY LABORATORY MARKERS

Antinuclear Antibodies (ANA) Diagnostic Patterns

  • Homogenous: Low specificity, associated with Anti-dsDNA.

  • Peripheral (rim): High specificity for SLE.

  • Centromere: Associated with CREST syndrome, SLE.

  • Speckled Patterns: Include various antibodies like Ro/SS-A (Sjögren's) and La/SS-B.

  • Nucleolar Patterns: Associated with scleroderma, primary biliary cirrhosis, autoimmune hepatitis.

SJOGREN’S SYNDROME

Overview

  • Immune-mediated dysfunction affecting exocrine glands (salivary, lacrimal, sebaceous).

  • Leads to reduced production of tears and saliva.

Laboratory Findings

  • Testing reveals:

    • SS-A (Anti-Ro) antibodies ~ 65% positive.

    • SS-B (Anti-La) antibodies ~ 65% positive.

    • ANA: Positive with a speckled pattern.

    • Rheumatoid Factor (RF): Positive in ~75% of cases.

  • Commonly seen in conjunction with RA, SLE, and autoimmune thyroid conditions.

  • CBC may reveal neutropenia and anemia.

SCLERODERMA

Characteristics

  • Defined by chronic progressive fibrosis and vascular dysfunction affecting skin and internal organs.

  • "Sclero" = hard, "derm" = skin.

  • More prevalent in women (2-3 times higher than men).

  • Typically presents in those aged 30-50.

  • Black and Native American populations may experience more severe forms.

Laboratory Testing for Limited Scleroderma

  • Tests usually include:

    • CBC: Look for anemia.

    • CMP: Assess overall metabolic function.

    • CRP/ESR: May or may not be elevated.

    • ANA: Most patients show a speckled pattern.

    • Anti-Centromere antibodies: Highly specific for CREST variant.

    • SCL-70 antibodies: Present in limited numbers of patients.

RHEUMATOID ARTHRITIS (RA)

Overview

  • Autoimmune condition leading to joint destruction, classified as a type III hypersensitivity reaction.

  • Common symptoms include joint pain, swelling, and decreased mobility, which improves with activity.

Laboratory Findings

  • Important tests for diagnosis:

    • Rheumatoid Factor (RF)

    • Anti-CCP Antibodies: Sensitivity up to 95-98%.

    • ESR and CRP: Often correlate with disease activity.

Clinical Distinction Between RA and Osteoarthritis (OA)

Feature

Rheumatoid Arthritis

Osteoarthritis

Primary Joints Affected

Metacarpophalangeal, Proximal Interphalangeal

Distal Interphalangeal

Joint Characteristics

Soft, warm, tender

Hard, bony

Stiffness

Worse after resting (morning stiffness)

Worse after effort (evening stiffness)

Laboratory Findings

Positive RF, Anti-CCP, Elevated ESR and CRP

RF-negative, Anti-CCP-negative, Normal ESR and CRP

DERMATOMYOSITIS / POLYMYOSITIS

Overview

  • Dermatomyositis: Skin manifestations with polymyositis criteria, characterized by:

    • Periorbital edema (heliotrope rash).

    • Gottron’s papules, dilated nailbed capillaries, scaly patches.

  • Polymyositis: Inflammatory myopathy affecting proximal muscles with weakness more than pain.

Laboratory Findings

  • CBC typically within normal limits (WNL).

  • CMP may show elevated liver function tests (LFTs).

  • Muscle enzymes (CK and Aldolase) typically elevated.

  • Inflammatory markers (CRP/ESR) often normal and not reliable.

  • ANA: Commonly positive.

  • Anti-Jo-1: Most common myositis-specific autoantibody.

ANTIPHOSPHOLIPID SYNDROME

Overview

  • Characterized by immunoglobulins (mostly IgG/IgM) against phospholipid-protein complexes leading to a hypercoagulable state.

  • Results in deep vein thrombosis (DVT) and can cause spontaneous abortions or fetal demise.

Laboratory Findings

  • Prolonged PTT that does not improve with mixing studies, indicating interference with phospholipid-dependent assays.

  • Presence of lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 GP I antibodies.

ANCA (ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES)

Overview

  • These are IgG autoantibodies against neutrophils and monocytes, associated primarily with vasculitis.

  • Two staining patterns observed:

    • P-ANCA (perinuclear): Associated with Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss), Microscopic Polyangiitis.

    • C-ANCA (cytoplasmic): Associated with Granulomatosis with Polyangiitis (Wegener’s granulomatosis).

HLA-B27

Overview

  • HLA-B27 is a Class I antigen often associated with Seronegative Spondyloarthropathies, which include:

    • Ankylosing Spondylitis

    • Psoriatic Arthritis

    • Reactive Arthritis

    • Inflammatory Bowel Disease (IBD).

ACUTE PHASE REACTANTS

Overview

  • Acute phase reactants develop in response to a range of inflammatory conditions, including infections, inflammatory diseases, and malignancies.

  • Generally non-specific indicators of inflammation.

Erythrocyte Sedimentation Rate (ESR)

  • Measures the rate at which red blood cells settle in a tube of blood, reflecting inflammation level.

  • Useful for detecting or tracking inflammatory conditions, though frequently non-specific.

  • In clinical practice, focus on trends over individual test results.

C-Reactive Protein (CRP)

  • An acute phase reactant primarily produced by the liver during inflammation or bacterial infections.

  • More sensitive than ESR and responds more quickly to changes in inflammation.

  • Elevated CRP can indicate increased cardiac risk factors.

Procalcitonin

  • Sensitive marker for bacterial infections, especially pneumonia and sepsis.

  • Its level in the bloodstream can indicate the body's response to infection.

TOXICOLOGY

Overview

  • Toxicology: the study of poisons, their actions, detection, and treatment of conditions resulting from exposure.

  • Major sources of drug poisoning/toxicity:

    • Approximately 50%: Suicide attempts

    • Approximately 30%: Accidental exposure (primarily children)

    • Approximately 20%: Occupational exposures, homicides.

Common Applications in Toxicology

  • Therapeutic Drug Monitoring: Aims to achieve maximum therapeutic efficacy while minimizing toxicity.

  • Emergent Testing for Drug Toxicity: Important for intentional and unintentional overdoses.

  • Identifying Drugs of Abuse: Includes workplace drug testing.

  • Environmental Toxins: Monitoring for toxic substances that contaminate the environment.

THERAPEUTIC DRUG MONITORING

Definition

  • The practice of measuring drug or metabolite concentrations to optimize dosing and assess compliance.

Purpose

  • To find the drug dosage that maximizes efficacy while minimizing toxicity.

Indications

  • When a drug has a narrow therapeutic index.

  • Situations with pharmacokinetic variability from patient to patient.

  • Concerns regarding patient compliance with medication regimens.

Therapeutic Index (TI)

  • The ratio of the dose of a drug that produces desired therapeutic effects to the dose that produces unwanted toxic effects.

  • Higher TI indicates better drug safety.

PHARMACOKINETICS

Overview

  • Study of drug disposition in the body, including:

    • Liberation: Release of the drug from its dosage form.

    • Absorption: Movement from the administration site into circulation.

    • Distribution: Reversible movement of the drug through circulation and body tissues.

    • Bioavailability: Proportion of the drug absorbed into systemic circulation.

    • Metabolism: Conversion of drug to active or inactive compounds, mainly in the liver.

    • Elimination: Excretion of the drug from the body, primarily via kidneys.

Half-Life and Steady State

  • Biological Half-Life: Approximately 5 half-lives are required to reach steady state (97% complete).

  • Steady State: Occurs when the amount of drug entering the system equals the amount being eliminated.

THERAPEUTIC RANGE

Definitions

  • Minimum Effective Concentration: Below this level, therapeutic effects are not achieved.

  • Minimum Toxic Concentration: Above this level, toxicity may occur.

Measurement of Trough and Peak Values

  • Trough Value: Lowest concentration achieved in a dosing cycle, should be above the minimum effective concentration.

  • Peak Value: Highest concentration achieved in a dosing cycle, should be below the minimum toxic concentration.

Trough and Peak Examples

  • Various drugs have specific half-lives influencing these values, impacting dosing schedules (e.g., Xanax, Methamphetamine, Lead, Mercury).

TOXICOLOGY SPECIMEN SELECTION

Guidelines

  • Selection of the best specimen depends on:

    • Timing and mode of exposure (ingested vs. injected).

    • Specimens can include:

    • Short time since ingestion: Gastric samples.

    • Moderate time since ingestion: Blood samples.

    • Extended time since ingestion: Urine samples.

TESTING FOR ACETAMINOPHEN TOXICITY

Rumack-Matthew Normogram

  • Graphical tool to assess the risk of toxicity based on serum acetaminophen levels and the time elapsed since ingestion.

  • Therapeutic range for acetaminophen is 10-30 mg/L.

DRUGS OF ABUSE

Testing Overview

  • Includes testing for illicit substances and potentially harmful therapeutic agents.

  • Commonly tested drugs include:

    • Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, heroin, THC, alcohol.

Testing Protocol

  • Typically involves two steps: screening followed by confirmatory tests, usually via urine or serum.

  • Factors that can affect test results include:

    • False Positives: Antibiolics, hyperglycemia, some medications.

    • False Negatives: Rare but can occur.

  • Methods to ensure sample validity like checking urine pH and specific gravity.

ENVIRONMENTAL TOXINS

Carbon Monoxide

  • An odorless and nonirritating gas, a leading cause of accidental and deliberate poisonings.

  • Mechanism: Binds to oxygen-binding sites in hemoglobin.

  • Symptoms include impaired vision, hearing, cardiac dysrhythmias, and headache.

  • Lab Testing: Measure carboxyhemoglobin levels in arterial blood.

Lead Poisoning (Plumbism)

  • Symptoms: anemia, behavioral issues, seizures, mental retardation, renal toxicity.

  • Antidotes: EDTA, penicillamine, and other chelating agents.

  • Diagnosis: Blood tests, with levels < 5 mcg/dL in children monitored periodically.