Clinical Lab Diagnosis - Rheumatology Lecture

When to order Rheumatology / Immunology Labs

joint swelling, low grade fever, persistent fatigue, weakness, arthritis-like pain in one or more joints, red rash (for lupus, one resembling a butterfly across the nose and cheeks), skin sensitivity to light, hair loss, muscle pain, numbness or tingling in the hands or feet, inflammation and damage to organs and tissues (including the kidneys, lungs, heart, lining of the heart, central nervous system, and blood vessels)

What are the 3 large categories for Rheumatology?

Inflammatory, Non-Inflammatory, Non-Articular

What is the inflammatory category?

Swelling and joint pain, usually poly-articular

Includes gout, RA, lupus, etc

Often an auto-immune condition

What is the non-inflammatory category?

Joint pain

Includes OA

often a history of trauma

What is the non-articular category?

Arthralgia, myalgia

Including bursitis, tendonitis, strain, etc

Often a history of trauma

American Autoimmune Related Disease Association - Disease List

Addison disease

Antiphospholipid Syndrome

Autoimmune Hepatitis

Celiac disease

Graves disease

Guillain0Barre Syndrome

Hashimoto Thyroiditis

Inflammatory bowel disease

Multiple Sclerosis

Myasthenia gravis

Pernicious Anemia

Giant Cell Arteritis/Temporal Arteritis

Primary Biliary Cirrhosis

Sclerosing cholangitis

Reactive arthritis

Rheumatoid arthritis

Sarcoiditis

Scleroderma

Sjrogen Syndrome

Lupus

Type 1 diabetes

Vasculitis

What are the Biomarkers of Inflammation?

CRP (C-reactive protein), ESR (Erythrocyte Sedimentation Rate), HS-CRP Test (Highly Sensitive C-reactive protein), Autoantibodies, Systemic Autoantibodies, Organ Specific Autoantibodies

What is C-reactive protein? (CRP)

Made in liver

Sensitive, but non-specific indicator of inflammation from autoimmune diseases

(Also elevates following MI, sepsis, etc)

Becomes elevated in Acute Inflammatory States

(Dissipates once the inflammation subsides)

(Rises 6 hours after tissue damage and has a 48 hour half life)

Good for acute monitoring

What is Erythrocyte Sedimentation Rate? (ESR)

Increases as a result of any cause or focus of inflammation.

When an inflammatory process is present, fibrogen enters the blood in high amounts and causes red cells to stick to each other, which raises THIS level.

Only tells you that there is probable inflammation somewhere in the body

Rises 24-48 hours following tissue damage

Has 4-6 day half life

Good for chronic monitoring

Which biomarker is good for acute monitoring?

CRP

Which biomarker is good for chronic monitoring?

ESR

What is the half-life of CRP?

48 hours

How long after tissue damage does CRP rise?

6 hours

What is the half-life of ESR?

4-6 days

How long after tissue damage does ESR rise?

24-48 hours

what is Highly Sensitive CRP?

Detects lower levels and is an indicator of Mi risk

Autoantibodies

Order when chronic, progressive arthritic symptoms, fever, fatigue, muscle weakness, and/or a rash that cannot readily be explained

What are some of the systemic autoantibodies?

(Think everything in the nucleus of a cell)

Antinuclear Antibodies (ANA)

Antineutrophil Cytoplasmic Antibodies (ANCA)

Anti-Double Stranded DNS (anti-dsDNA)

Anticentromere Antibodies (ACA)

Antihistone Antibodies

Cyclic Citrullinated Peptide Antibodies (CCP)

Extractable Nuclear Antigen Antibodies (e.g. anti-SS-A (Ro) and anti-SS-B (La), anti-RNP, anti-Jo-1, anti-Sm, Scl-70)

Rheumatoid Factor (RF)

What are the categories of Organ Specific Autoantibodies?

Clotting (coagulation) system,

Endocrine/metabolic system

Gastrointestinal Tract

Thyroid

Liver

Kidney

Muscles

What falls within the Clotting (coagulation) system?

Cardiolipin Antibodies

Beta-2 Glycoprotein 1 Antibodies

Antiphospholipid Antibodies (APA)

Lupus anticoagulants (LA)

What falls within the Endocrine/metabolic system?

Islet Autoantibodies in Diabetes

Insulin antibodies

What falls within the Gastrointestinal tract category?

Anti-Tissue Transglutaminase (anti-tTG) and Anti-Gliadin Antibodies (AGA)

Intrinsic Factor Antibodies

Parietal Cell Antibodies

What falls within the Thyroid category?

Thyroid autoantibodies (e.g. anti-TPO, TSH receptor antibodies like TSI)

What falls within the Liver category?

Smooth Muscle Antibodies (SMA) and F-actin Antibody

Antimitochondrial Antibodies (AMA) and AMA M2

liver Kidney Microsome Type 1 Antibodies (anti-LMK-1)

What falls within the Kidney category?

Anti-Glomerular Basement Membrane (GBM)

What falls within the Muscles category?

Acetylcholine Receptor (AChR) Antibodies

What are the Selected Tests?

Rheumatoid Factor

Anti Cyclic Citrullinated Peptide Antibody (Anti-CCP)

Anti-Nuclear Antibodies

Anti-Double-Stranded DNA Antibodies

HLA-B27 Antigen Test

What is Rheumatoid Factor?

Used to detect RA

Because the sensitivity and specificity of THIS test are not ideal, other laboratory tests are often performed in conjunction with THIS test

About 80% of those with RA will test positive for THIS test, but it can be negative in people who have clinical signs of RA

What is Anti Cyclic Citrullinated Peptide Antibody?

THIS antibody test has a sensitivity and specificity that is considered better than the other test for this condition and is more likely to be positive with early RA

But there is increases sensitivity when both tests are used together, which allows for earlier disease detection

THESE antibodies are autoantibodies produced by the immune system that are directed against peptides of the same name and detects / measures the antibodies in the blood

This peptide is naturally produced in the body as part of the metabolism of the amino acid arginine.

However, in joints with RA, this conversion might happen at a higher rate. THIS peptide changes the protein structure and can trigger an immune response, producing antibodies against joint proteins

What are Anti-Nuclear Antibodies? (ANA)

THIS test may be positive with several autoimmune disorders

Patients with SLE (Systemic Lupus Erythematosus) are almost always positive for THIS test

But some healthy people may also be positive for THIS test at low levels

There are follow up tests for THIS test which are the nucleus specific tests

What are Anti-Double Stranded DNA Antibodies?

Hallmark of SLE

The sensitivity is 70% and the specificity is 95%

What is the sensitivity of Anti-dsDNA?

70%

What is the specificity of Anti-dsDNA?

95%

What is the HLA-B27 Antigen test?

Correlates to an increased risk of Ankylosing Spondylitis and other autoimmune arthritides

e.g. ankylosing spondylitis, reactive arthritis (Reiter Syndrome), Juvenile RA, inflammatory bowel disease

Found in 6% of the population

80-90% of AS patients

Those with a negative test probably do not have AS

What percentage of the population is HLA-B27 found?

6%

What percentage of Ankylosing spondylitis (AS) is HLA-B27 found?

80-90%

Are those with a negative HLA-B27 test likely to have AS?

no

What is the 2010 rheumatoid arthritis classification criteria?

Involvement of swollen and tender joints

Serotology

Duration of synovitis

Acute-phase reactants

What falls within the “Involvement of swollen and tender joints” category in order of 0-5?

1 medium-large joint

2-10 medium-large joints

1-3 small joints

4-10 small joints

Greater than 10 joints (at least 1 must be small)

How many points is 1 medium-large joint worth?

0

How many points is 2-10 medium-large joints worth?

1

How many points is 1-3 small joints worth?

2

How many points is 4-10 small joints worth?

3

How many points is greater than 10 joints (at least 1 small joint) worth?

5

What falls within the “serology” category in order of 0-3?

Neither RF nor ACPA positive

One low-positive titer on at least one test

One high-positive titer on at least one test

How many points is “neither RF nor ACPA positive” worth?

0

How many points is “one-low positive titer on at least one test” worth?

2

How many points is “one high positive titer on at least one test” worth?

3

What falls within the “duration of synovitis” category in order of 0-1?

Less than 6 weeks

6 weeks or longer

How many points is “less than 6 weeks” worth?

0

How many points is “6 weeks or longer” worth?

1

What falls within the “acute phase reactants” category in order of 0-1?

Neither CRP nor ESR abnormal

Abnormal CRP or abnormal ESR

How many points is “neither CRP nor ESR abnormal” worth?

0

How many points is “abnormal CRP or abnormal ESR” worth?

1

What is the criteria for the 1987 American College of Rheumatology?

Morning stiffness

Arthritis of three or more joint areas

Arthritis of hand joints

Symmetric arthritis

Rheumatoid nodules

Serum rheumatoid factor

Radiographic changes

What are the categories of Modified New York Criterial for the diagnosis of AS?

1. clinical

2. radiological

What falls under the “clinical” category for the NY criteria for the diagnosis of AS?

low back pain and stiffness > 3 months, which improves with exercise but NOT rest

limitation of lumbar spine in both saggital and frontal planes

limitation of chest expansion relative to normal for age and sex

What falls under the “radiological” category for the NY criteria for the diagnosis of AS?

bilateral sacrolitis > grade 2

unilateral sacrolitis > grade 3 or 4

AS is present if the radiological criterion is associated with at least one clinical criterion

What is the grading for sacrolitis?

0-4

What is grade 0 for sacrolitis?

normal

What is grade 1 for sacrolitis?

suspicious

What is grade 2 for sacrolitis?

sclerosis, some erosions

What is grade 3 for sacrolitis?

severe erosions, widening of the joint space, some ankylosis

What is grade 4 for sacrolitis?

complete ankylosis

What is the CASPAR criteria for Psoriatic-Arthritis?

1. evidence of psoriasis

2. psoriatic nail dystrophy

3. negative test result for rheumatoid factor

4. dactylitis

5. radiographic evidence of junta-articular new bone formation

to met the CASPAR criteria for PsA, a patient must have inflammatory articular disease AND score greater or equal to 3 points based on the above categories

What are the MAJOR criteria for reactive arthritis?

1. arthritis with 2 of 3 of the following:

   1. asymmetric

   2. mono- or oligoarthritis

   3. affection predominantly in lower limbs

2. Preceding symptomatic infection, with 1 or 2 of the following findings

   1. enteritis (diarrhea for at least 1 day, 3 days to 6 weeks BEFORE the onset of arthritis)

   2. urethritis (dysuria or discharge for at least 1 day, 3 days to 6 weeks BEFORE the onset of arthritis

What are the MINOR criteria for reactive arthritis?

1. evidence of triggering infection

   1. positive nucleic acid amplification test in the morning urine or urethral/cervical swab for chlamydia trachomatis

   2. positive stool culture for enteric pathogens associated with ReA

2. evidence of persistent synovial infection (positive immunohistology or PCR for chlamydia)

How to define reactive arthritis (ReA)

Definite reactive arthritis: BOTH major criteria AND relevant minor criteria

Probable reactive arthritis: BOTH major criteria BUT not relevant minor criteria OR major criteria #1 AND one or more of the minor criteria

What is the exclusion criteria for reactive arthritis?

other causes for acute arthritis

What are the Arthrotides; Seronegative Spondyloarthropathies?

Ankylosing Spondy (AS)

Psoriatic Arthritis

Reactive Arthritis

Ulcerative Collitis

Crohn’s Disease

Irritable Bowel Disease (IBD)

Celiac Disease

Systemic Lupus Eritematous (SLE)

What are the clinical features of Ulcerative Colitis (UC)?

Frequent small-volume diarrhea with urgency

Predominately bloody diarrhea

What are the endoscopic and radiological features of UC?

Diffuse superficial colonic inflammation?

Involvement of rectum, but this can be patchy

Shallow erosions and ulcers

Spontaneous bleeding

What are the histopathological features of UC?

Diffuse inflammation in mucosa or submucosa

Crypt architecture distortion

What are the serological markers of UC?

Antineutrophil cytoplasmic antibodies

What are the clinical features of Crohn’s Disease (CD)?

Diarrhea accompanied by abdominal pain and malnutrition

Abdominal mass

What are the endoscopic and radiological features of CD?

Perianal lesions

Discontinuous transmural asymmetric lesions

Mainly involving the ileum and right sided colon

Cobblestone appearance

Longitudinal ulcer

Deep fissures

What are the histopathological features of CD?

Granulomatous inflammation

Fissures or aphthous ulcers can be seen; often transmural inflammation

What are the serological markers for CD?

Anti-Saccharomyces cerevisiae and other antibodies to microbial antigens

What are the rheumatological manifestations of Irritable Bowel Disease (IBD)?

1. peripheral arthritis

2. axial involvement (low back pain, SI (sacro-iliitis), spondylitis, true AS (ankylosing spondylitis))

3. enthesitis

4. secondary HOA (hypertrophic osteoarthropathy)

5. secondary osteoporosis

What re the blood tests for Celiac Disease?

IgA tTG with total IgA

What do you order in patients with suspected celiac disease and an IgA deficiency?

IgG deaminated gliadin peptide

What do you order in patients with suspected celiac disease and IgA tTG positive with normal total IgA?

small bowel biopsy

What do you order in patients with suspected celiac disease and normal IgA tTG and normal total IgA?

nothing unless suspicion for celiac disease remains, then order small bowel biopsy

What are the clinical criteria for systemic lupus eritematous (SLE)?

1. acute cutaneous lupus

2. chronic cutaneous lupus

3. oral or nasal ulcers

4. non-scarring alopecia

5. arthritis

6. serositis

7. renal

8. neurologic

9. hemolytic anemia

10. leukopenia

11. thrombocytopenia (<100,000/mm³)

What are the immunologic criteria for systemic lupus eritematous (SLE)?

1. ANA

2. anti-DNA

3. anti-Sm

4. Antiphospholipid Ab

5. Low complement (C3, C4, CH50)

6. direct Coombs’ test (do not count in the presence of hemolytic anemia)

What are the requirements for SLE?

Requirements: greater or equal to 4 criteria (at least 1 clinical and 1 laboratory criteria) Or biopsy-proven lupus nephritis with positive ANA OR Anti-DNA