ARTHRITIS TESTING
Ed Friedlander, M.D., Pathologist
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KCUMB Students
"Big Robbins" -- Bones / Joints / Soft Tissue Tumors
Lectures follow Textbook

INTRODUCTION TO ARTHRITIS TESTING

SYNOVIAL FLUID (JAMA 264: 1009, 1990, still the best)

SYNOVIAL FLUID CELLS

SYNOVIAL FLUID CRYSTALS

SYNOVIAL FLUID MUCIN-CLOT ("Ropes test")

Inflammation in the joint space damages the hyaluronic polymers, shortening them.

SYNOVIAL FLUID STRING TEST ("Viscosity test")

OTHER TESTS ON SYNOVIAL FLUID

SERUM RHEUMATOID FACTOR (RF)

ANTI-CCP ANTIBODIES (anti-cyclic citrullinated antibodies; now anti-CCP1 and anti-CCP2; updates Rheumatology 45: 478, 2006; Ann. Rheum. Dis. 65: 845, 2006; J. Imm. 175: 5575, 2005)

ANTI-NUCLEAR ANTIBODIES ("ANA's"): Pathology evidence-based consensus document Arch. Path. Lab. Med. 124: 71, 2000. Simple update: J. Allerg. Clin. Imm. 117(2): S-445, 2005.
RIM PATTERN Probably anti-dsDNA. Your patient probably has SYSTEMIC LUPUS.
HOMOGENEOUS PATTERN Probably anti-histones. Your patient probably has DRUG-INDUCED LUPUS.
SPECKLED PATTERN Could be anti-Sm and/or anti-Ro/SSA and/or anti-La/SSB and/or anti-U1snRNP and/or any of several others, or nothing at all that anybody knows. You'll need to decide whether to continue your workup!
CENTROMERE PATTERN An especially fine speckling with little background staining. This is anti-centromere, the marker for CREST / pulmonary hypertension.
NUCLEOLAR PATTERN anti-Th/To or anti-fibrillarin / anti-U3snRNP or anti-U17RNP. Think of SCLERODERMA, though most scleroderma patients don't show the nucleolar pattern.

{33205} positive lupus band test

{29557} ANA, speckled pattern
{33154} ANA, rim pattern
{33248} ANA, nucleolar pattern
{08457} ANA, nucleolar pattern

SOME LABS TO KNOW

TEST

USEFUL IN SUSPECTED
COMMENTS

Tapping the joint

Consider doing this especially when there is a hot joint with an effusion

Heparin tube for crystals and CBC-diff;

Plain tube(s) for viscosity, mucin clot, complement, glucose, gram stain, and culture

* Synovial fluid complement

Acute lupus, acute RA

Likely to be low in active autoimmune disease.

* Synovial fluid RF

Early adult RA

Becomes positive before serum RA. Limited usefulness.

Serum rheumatoid factor

Adult RA

75% of adult RA's will be positive

Many positives in old age, SLE, SBE, syphilis

Negative in juvenile arthritis, osteoarthritis, others

* Serum IgG RF

Adult RA

Available. Of doubtful value.

* Serum anti-RANA

Adult RA

Old test based on the idea that Epstein-Barr virus causes many cases of rheumatoid arthritis, an idea that is still floating around after decades.

Serum f-ANA

Those multi-organ autoimmune diseases

Screening test. Titers 1:20 to 1:160 are nonspecific.

Rim: Classic lupus

Speckled: Classic lupus, Sjogren's, MCTD, others

Homogeneous: Drug-induced lupus

Nucleolar: Scleroderma ... again, this is NOT specific (J. Clin. Path. 61: 283, 2008)

Serum anti-dsDNA

SLE

Same as anti-nDNA and anti-DNA. Higher titers are very specific for lupus. Rising titers predict an exacerbation. Titers fall on successful treatment.

Now being seen after infliximab therapy also. Stay tuned.

Serum C3

SLE

Usually low in lupus; of course this is not specific. Value rises to normal on successful treatment

Serum anti-Sm

SLE

Very specific for lupus, positive in 30% of cases.

Serum anti-histone

Drug-induced lupus

Most patients with this antibody remain asymptomatic. A negative value pretty much rules out drug-induced lupus.

Lupus band test

SLE

Requires skin biopsy. Becoming obsolete

Serum anti-snRNP

Mixed CT disease

All MCTD's positive, low titers in other diseases. Ask whether the lab can give you just an anti-U1.

* Serum anti-centriole

Scleroderma

Promoted as positive in some patients with scleroderma; not much used nowadays

Serum anti-centromere

CREST

High titer defines CREST syndrome

Serum anti-SSA (-Ro)

Sjogren's

Often positive but not specific. This is the autoantibody that causes neonatal lupus with heart block.

Serum anti-SSB (-La)

Sjogren's

Often positive but not specific

* Serum anti-adrenal

Autoimmune Addison's

Helps rule out other causes of Addisonism. The antigen is (at least usually) 21-hydroxylase.

* Serum anti-islet-cell

New or impending DM type I

Usually positive, doubtful clinical usefulness

Serum anti-insulin receptor

Type II diabetes variant

Insulin resistance caused by blocking autoantibody

Serum anti-sperm antibodies

Infertility

Husband or wife

Serum anti-AchR

Myasthenia gravis

Anti-acetyl cholinesterase receptor. The first test to order in suspected MG.

* False positives occur in patients injected with bungarotoxin (cobra venom, quack remedy)

Serum anti-AchR Blocking Ab

Myasthenia gravis

Order in suspected MG if Anti-AchR is negative

* Serum anti-striational ab's (StrAbs; anti-titin, anti-ryanodine reeptor)

Myasthenia gravis, thymoma is usually present

If negative in MG, some surgeons will not remove thymus. See Arch. Neurol. 62: 442, 2005.

* Serum Kv1.4 (potassium channel)

Myasthenia gravis

New possible marker for more serious disease (Arch. Neuro. 64: 1121, 2007)

Serum anti-GBM

Goodpasture's

A few false negatives. If the pathologist who does the test isn't experienced, there will be lots and lots of false positives.

Serum anti-tubular BM

Renal interstitial disease

Anti-TMB disease is an important, under-recognized cause of acute interstitial nephritis.

* Serum anti-intrinsic factor

Pernicious anemia

Probably worthless, less sensitive and less specific than a Schilling test

* Serum anti-parietal cell abs

Pernicious anemia

Probably worthless, less sensitive and less specific than a Schilling test

Schilling test

Pernicious anemia etc.

It's a shame when the reagents aren't available -- here's hoping this good test will be re-instituted

Step 1: Give your patient radioactive vitamin B12 by mouth. See how much comes out in the urine. If very little comes out in the urine, your patient can't absorb straight vitamin B12 (pernicious anemia, fish tapeworm, or ileal disease).

Step 2: If your patient just proved he or she cannot absorb straight vitamin B12, repeat the test by administering a mix of vitamin B12 and intrinsic factor. If, this time, the patient excretes more of the vitamin B12 in the urine, you have established the diagnosis of addisonian pernicious anemia.

Check your protocol. You'll probably want to administer an injection of vitamin B12 before the test, since you don't want the patient actually storing the radioactive substance.

Platelet-associated Ig

Immune thrombocytopenia

Idiopathic thrombocytopenic purpura, also SLE, AIDS

Serum anti-skin

Blistering diseases

Inter-epithelial antibodies: Pemphigus vulgaris

Dermal-epidermal junction: Bullous pemphigoid

Reticulin: Dermatitis herpetiformis (biopsy it instead!)

* Serum anti-reticulin

* Serum anti-endomysium

* Serum anti-gliadin

Sprue / dermatitis herpetiformis

Nowadays some clinicians omit small bowel biopsy when these are positive, and move right to the gluten-free diet trial.

* Anti-collagen (I, IV, etc.)

Various joint diseases Research interest only; nothing's really come of these in humans despite decades of work.

Serum anti-smooth muscle

Lupoid hepatitis 1

Only high titers are significant, low titers occur in many diseases

Serum anti-LKM1 ("liver kidney microsome")

"Lupoid hepatitis" 2

Defines the illness

Anti-liver-kidney-microsome disease.

Serum anti-mitochondrial

Primary biliary cirrhosis

Sensitive and specific, but only high titers are significant health threats

* Serum anti-myocardial

"Dressler's"

Completely out of use. The existence of Dressler's is very much in doubt anyway.

Serum anti-streptococcal

Sequelae of strep infection

Glomerulonephritis, rheumatic fever. Several tests are available, ask you lab ("ASO", "anti-hyaluronidase" are popular). They will be positive by the time your patient has rheumatic fever or glomerulonephritis.

* Serum anti-teichoic acid

Staph infections

This used to be used to monitor the treatment of osteomyelitis, but is now completely out of use which is fine (Ped. Inf. Dis. J. 17: 1021, 1998)

Serum anti-neutrophil cytoplasmic antigen

Wegener's, polyarteritis

Anti-myeloperoxidase (p-ANCA, p-ACPA) causes many cases of polyarteritis (the "small vessel" variant, now clearly a distinct disease from "classic polyarteritis nodosa"). You'll also see it in most patients with the combination of sclerosing cholangitis and ulcerative colitis.

Anti-proteinase 3 (c-ANCA, c-ACPA) is closely linked to Wegener's granulomatosis.

You can see these in various systemic autoimmune diseases; whatever the "underlying systemic vasculitis.

Certain nonspecific ANCA's probably result from longstanding inflammation, as in rheumatoid arthritis (Art. Rheum. 36: 994, 1993).

Serum C' esterase inhibitor

Hereditary angioedema

Ask for both level and functional assay

Serum complement components

Deficiency states

Deficiencies of C1q, C1r, C1s, C4, C2, C5, and/or C8 simulate SLE

Deficiency of C6, C7, C8 have recurrent neisserial infections

In seeking out genetic birth defects, ask for both level and functional assay.

You can of course also use C3 and C4 to monitor the course of lupus.

Serum CH-50

Screening test for all complement component deficiencies ("titer that hemolyzes 50% of the test red cells")

Has also been used to follow the course of SLE

Serum anti-cardiolipin

SLE, AIDS, aborters, clotters

Newly recognized major disease, with thrombosis and abortion. Also called anti-phospholipid. Biochemically similar (but not identical to) "lupus anticoagulant" and the lupus biologic false positive for syphilis.

Nitroblue Tetrazolium test

Chronic granulomatous disease (i.e., the neutrophil killing defect)

Hereditary immunodeficiency syndrome with defective killing of staphylococci by polys

Serum anti-allergen IgE

Food or penicillin allergy

"RAST", supposed to replace skin tests, expensive.

* Raji cell assay

Circulating immune complexes

Limited usefulness

HLA-B27

Ankylosing spondylitis, etc.

Classic example of a result that is unlikely to affect patient management

* Von Willebrand factor

Vasculitis

In patients who do not have von Willebrand's disease but who do have some kind of serious systemic vasculitis (lupus, polyarteritis nodosa, Wegener's, Henoch-Schonlein, and so forth), levels of vWFAg are likely to be elevated (why? Arch. Dis. Child. 70: 40, 1994)

* Thrombomodulin

Vasculitis

Endothelial thrombin receptor. Serum levels increase in vasculitis (Am. J. Clin. Path. 101: 109, 1994)

Complement 3 nephritic factor

Membranoproliferative glomerulonephritis types I and (now) II

Pathogenic; helps establish the diagnosis

INFECTIOUS MONONUCLEOSIS REVIEW!

Roundsmanship!

"Heterophile antibodies"

Many inflammatory diseases

Agglutinate sheep red cells. Nobody orders this test.

Forsmann antibodies

Many inflammatory diseases

Heterophile antibodies that are absorbed by guinea pig kidney but not by beef RBC's. Nobody orders this test.

Mono test ("Mono-spot")

EB-virus infectious mono

Heterophile antibodies that are absorbed by beef RBC's, not by guinea pig kidney. Cheap test, sensitive and specific, but often remains negative for many weeks, often never turns positive in children

Serum IgG anti-EBV capsid

EBV infection, past/present

Expensive, high titers suggest current infection. This is the test to order if the "Mono-spot" is still negative but you still suspect EBV mono.

Serum IgM anti-EBV capsid

Current EBV infection

Sensitive and specific, very useful in children

EBV "early antigens"

Early or chronic EBV disease

Ask your infectious disease expert whether these tests are useful.

CMV, toxoplasmosis, HIV tests

Remember these too in "infectious mononucleosis"; "post-viral fatigue syndrome"

BIBLIOGRAPHY / FURTHER READING

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