1. Diagnostic Tests in Rheumatology: What Test Should I Order When?
Paul D. Simmons, MD
St. Mary’s Family Medicine Residency Program
Grand Junction, Colorado

2. Objectives
Present an rational approach to diagnosing the patient with rheumatologic disease.
Discuss history and physical exam features that can narrow the differential diagnosis.
Discuss the serologic tests that are most useful (i.e., have the best predictive value) in diagnosing various rheumatologic diseases.

3. Case Presentation
A 45-year-old woman presented to her local hospital with a 2-year history of asymmetric migratory arthralgias involving the left knee, ankles, elbows, and fingers. She also had morning stiffness, increasing fatigue, an erythematous, nonpruritic rash after sun exposure, and a 3-month history of chest pain that was relieved when she was in an upright position. She did not have fevers, dry eyes or mouth, oral ulcers, or eye irritation or pain.

4. What is your differential diagnosis at this point?
What additional information do you need?

5. Text
Gregory House, of Fox TV’s “House”

6. Historical Clues to Rheumatic Disease
Demographics: age, gender, ethnicity.
African-American <40 years old: think sarcoidosis.
White female >50 years old: think giant cell arteritis, polymyalgia rheumatica or OA.
Patterns of Joint Involvement: Mono-, Oligo- or Poly-? Axial or Peripheral? Migratory?
Peripheral monoarthritis: think gout, pseudogout or OA.
Symmetric polyarthritis: think SLE, RA, systemic sclerosis or psoriatic arthritis.
Axial oligoarthritis: think Reiter’s syndrome (now called reactive arthritis) or ankylosing spondylitis.

7. Question 1 The picture suggests what diagnosis? 1. SLE 2. Acute gout
3. OA
4. Sjogren’s syndrome

8. Physical Examination
In patients with potential rheumatologic disease, examine:
GEN: cachexia, posture, kyphosis or lordosis?
HEENT: conjunctival involvement, iritis, scleritis, temporal tenderness, xerostomia, apthous ulcers?
NECK: thyroid normal, lymphadenopathy?
CV: arterial pulses, bilateral blood pressures asymmetric?
LUNGS: wheezing, dyspnea, cough?
ABD: hepatomegaly, aneurysms, renal bruit?
MSK: all joints, synovitis, symmetry, deformity, crepitus?
SKIN: ulcers, rashes, petechiae, abnormal coloration, edema?

9. What is your diagnosis?
(Patient also has dysphagia and painful, blue fingers if exposed to the cold.)

10. Think: graceful bird in the wolf’s disease.

11. Young woman with a facial rash. Not to mention only half a head.

12. What is this patient’s platelet count?

13. Can’t pee, can’t see, can’t climb a tree...
This patient recovered from a illness with bloody diarrhea one month ago. He is complaining of dysuria and knee pain.
Can’t pee, can’t see, can’t climb a tree...

14. Case Presentation (cont.)
No personal or family history of inflammatory disorders.
Meds: fluoxetine, at a dose of 40 mg once daily; and estrogen therapy (initiated after the patient underwent hysterectomy for benign disease at 32 years of age). She took a nonsteroidal antiinflammatory drug on an as-needed basis.
PE: She is afebrile. BP 150/84 mm Hg. HR 100 beats per minute and regular. There was no malar rash, mucous membrane ulceration, or cervical, supraclavicular, axillary, or inguinal adenopathy. Cardiovascular and chest examinations were normal. Both wrists and the left knee were tender; the left knee had a palpable effusion. The patient's grip strength was normal bilaterally. There were no signs of impaired salivary gland function (i.e., cheilosis or loss of glistening of the tongue or mucous membranes).

15. What is in your differential now?
Are there any laboratory or imaging tests you would like to order?

16. A Few Options Rheumatoid factor (RF) Anti-nuclear antibody (ANA)
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Others:
Anti-dsDNA
Anti-histone
Anti-U1 snRNP
Anti-Sm
Anti-Ro (anti-SS-A)
Anti-La (anti-SS-B)
Anti-ribosome
Anti-centromere
Anti-topoisomerase I (anti-ScL-70)
Anti-Jo 1
Antiphospholipid
Anticardiolipin
Lupus anticoagulant
Anti-cyclic citrullinated peptide (anti-CCP)

17. Question 2
A 50 year old woman with bilateral knee pain (and no other complaints) presents for follow-up. At her previous visit, your partner ordered an ESR and a RF. The ESR is 30 mm/hr and the RF is positive. You tell this patient:
1. “Ma’am, you definitely have rheumatoid arthritis.”
2. “Ma’am, you most likely have rheumatoid arthritis.”
3. “Ma’am, you certainly do not have rheumatoid arthritis.”
4. “Ma’am, I have no idea why my partner ordered these tests.”

18. Take Home Point #1: Serologic tests for rheumatologic diseases are SUPPORTIVE rather than DIAGNOSTIC.

19. Take Home Point 1b: This is so because--high incidence of false (+) in general population and low PPV in low-prevalence populations.

20. So, when do I order what?

21. ESR and CRP
These tests are most useful when you are RULING OUT an inflammatory disease, but they are non- specific if positive. (They are sensitive...SnNOUT...remember?)
Ex: In a meta-analysis involving 941 patients tested with an ESR for temporal arteritis, the LR+ was 1.1 (i.e., essentially useless), but the LR- was 0.2 (useful!).
In other words, if your pre-test probability for temporal arteritis was 50%:
your post-test probability with an abnormal ESR would be...50%
your post-test probability with a normal ESR would be 18%.

22. Case Presentation (cont.)
ESR: 100 mm/hr
CRP: 3.2 mg/dL
Some other labs:
Hgb 11.5 g/dL (MCV 86 per um^3)
WBC 9500 per mm^3
Plts 425,000 per mm^3

23. An Example of an Overused Test: Rheumatoid Factor
RA (50-90%)
SLE (15-35%)
Sjogren’s syndrome (75-95%)
Systemic sclerosis (20-30%)
Polymyositis/dermatomyositis (5-10%)
Cryoglobulinemia (40-100%)
MCTD (50-60%)
Age >70 yo (10-25%)
Bacterial endocarditis (25-50%)
Hepatitis (15-40%)
Sarcoidosis (3-33%)
Pulmonary silicosis (30-50%)
Primary biliary cirrhosis (45-70%)
Malignancy (5-25%)

24. Rheumatoid Factor Probably should rarely order this test. Pretest Prob
From Shmerling R., Am J Med 1991.
Pretest Prob
Posttest Prob with (+) RF
Posttest Prob with (-) RF 1%
16%
0.2%
25%
84% 7%
50%
94%
17%
75%
98%
39%
90%
99%
65%
Assuming a sensitivity of 80% and specificity of 95% for RA (more recent data are sens 65% and spec 89%).

25. Anti-CCP Antibody
Early assays (ELISA) had sensitivity of 67% and specificity of 95% (compared to 69% and 85% for RF) - later generation assays are even better.
However, no test is perfect.
False positives seen in active TB, Sjogren’s, SLE, scleroderma, and poly- and dermatomyositis.
In these cases, however, titres lower than those seen in RA.

26. Take home point #2: anti-CCP antibody is currently the best test for RA in a patient with undifferentiated polyarthritis.

27. ANA
ANA is a very sensitive (95-100%) and non-specific (49-90%) test for SLE.
A positive ANA is insufficient to diagnose SLE.

28. Case Presentation (cont.)
RF: negative
ANA: negative
Complement (C3 and C4) levels: normal

29. Question 3
Which of the following is NOT one of the American Rheumatology Association’s diagnostic criteria for SLE?
a. Oral or nasopharyngeal ulcers.
b. Pleuritis or pericarditis.
c. Persistent proteinuria or cellular casts.
d. Either a positive antiphospholipid, anti-DNA or anti- Sm antibody test.
e. An abnormal ANA titre.
f. Both d. and e. are not part of the ARA criteria.
h. All of the above are part of the ARA criteria.

30. It’s Not Lupus - unless it is.
Must have 4 of the following 11 findings:
Malar rash (fixed, flat or raised erythema)
Discoid rash (raised, red, scaling patches)
Photosensitivity
Oral ulcers
Arthritis
Serositis (pleuritis or serositis)
Renal disorder (proteinuria or casts)
Neurologic disorder (seizures or psychosis)
Hematologic disorder (anemia, leukopenia, thrombocytopenia)
Immunologic disorder (positive APLA, anti-DNA, antiSm or false positive for syphilis)
(+) ANA
(c) Fox Television

31. Take Home Point #3: Before ordering an ANA on a patient with possible SLE, make sure you’ve got 3 out of 11 of the ARA criteria.

32. Question 4
For our case patient, which of these additional tests would you like to order?
1. anti-dsDNA and anti-centromere.
2. anti-Ro and anti-La.
3. anti-histone and anti-U1 snRNP.
4. anti-phospholipid and lupus anticoagulant.
5. all of the above.
6. none of the above.

33. The Test Most Useful In anti-dsDNA anti-histone drug-induced lupus
Cautions!/Comments
anti-dsDNA
lupus nephritis and determining active vs inactive SLE
Do not order anti-ssDNA.
anti-histone
drug-induced lupus
Useful in combination with anti-dsDNA (absent in drug-induced lupus)
anti-U1 snRNP
MCTD
non-specific
anti-Sm
SLE
highly specific, not sensitive
anti-Ro
Sjogren’s, “ANA-negative” SLE
Congenital heart block in (+) mom
anti-La
Sjogren’s
Usually with anti-Ro
anti-ribosome
SLE (neuropsych)
anti-centromere
CREST
anti-topoisomerase I
Scleroderma
anti-Jo 1
Polymyositis/dermatomyositis
anti-phospholipid
APLA syndrome
recurrent fetal loss

34. anti-dsDNA and anti-histone
Useful in SLE to differentiate active (high +) SLE vs inactive (low + or neg).
Useful in distinguishing drug-induced lupus (anti-histone negative) vs. non- drug-induced lupus.
REMEMBER: dsDNA and histone proteins are both nuclear components, and SLE attacks DNA!

35. Anti-Ro (-SSA) and Anti-La (-SSB)
Nuclear - SLE, RA, DIL
Rim/Peripheral - SLE
First described in 1969 by Reichlin, Ab to “extractable nuclear antigens,” named after first patients who had them.
Speckled - SLE, Sjogren’s, scleroderma
Nucleolar - scleroderma, Raynaud’s

36. anti-centromere
CREST syndrome (calcinosis cutis, Raynaud’s*, esophageal dysmotility, sclerodactyly, telangiectasias), a distinct subtype of systemic sclerosis (scleroderma).
*French physician Maurice Raynaud (1834–1881)

37. anti-Jo 1 Polymyositis/Dermatomyositis: Gottron’s papules
Periorbital helitropic rash
Weakness, tenderness, proximal atrophy

38. anti-phospholipid Anti-phospholipid antibody syndrome
Ab directed against phospholipid- binding proteins that usually bind to endothelial cell membranes and keep them from being “sticky.”
Thrombosis and (in pregnancy) fetal loss.

39. Comprehension Question 1
Which ONE of the following is NOT a useful serologic test in suspected SLE?
1. anti-dsDNA
2. anti-histone
3. anti-Jo 1
4. ANA

40. Comprehension Question 2
While you were on vacation, your partner referred a patient to a rheumatologist for “keratoconjunctivitis sicca”. A lab arrives in your box noting “a speckled pattern on immunofluorescence consistent with anti-Ro and anti-La antibodies.” What is the most likely diagnosis for this patient?
1. SLE
2. RA
3. Anti-phospholipid antibody syndrome
4. Sjogren’s syndrome

41. Comprehension Question 3
A young woman just returned from climbing the south face of K2 with a malar rash, joint pain and fatigue. She was treated on the expedition with hydralazine for HAPE, but you’re also concerned about SLE. What test combination may help distinguish between drug- induced lupus and SLE?
1. ANA and anti-CCP antibody
2. ANA and RF
3. anti-dsDNA and anti-histone
4. anti-Ro and anti-La

42. Take Home Point #4: Most rheumatologic serologies are specific, but not sensitive. That is, they are useful in CONFIRMING a likely diagnosis. (SpPIN, remember?)

43. What have we learned?
Before ordering serologic tests, do a history and physical to narrow down your DDx.
Given that (a) most family practice patients with joint complaints DON’T have an autoimmune rheumatologic disease and (b) because the serologies have frequent false (+) results, never screen with antibody serologies.

44. What have we learned?
Anti-CCP antibody is a useful confirmatory test in the patient with polyarthritis thought to be RA.
To diagnose SLE, look to the ARA criteria (which are mostly H&P items), not just to the ANA.
The unusual serologies (anti-U1 snRNP, anti-Ro, etc.) are best used to clinch a likely diagnosis.

45. What have we learned? Lame Mnemonics if You Want Them:
ANA, anti-dsDNA, anti-Sm and anti-histone = lupus vs drug-induced lupus. (nuclear, DNA and histones)
anti-CCP = RA (the CCCP was RussiA)
anti-Ro and anti-La = Sjogren’s (RoLa-on antiperspirant keeps you dry!)
anti-centromere = CREST
anti-topoisomerase (ScL-70) = scleroderma
anti-Jo 1 = poly- and dermato-myositis (Jo, po, dermato...)
anti-phospholipid = APLA syndrome (duh...)

46. Case Resolution So whatever happened to our case presentation patient?
This case was from the NEJM (1/4/07) - Final Dx: Whipple’s disease (infection with Tropheryma whippelii), which causes arthralgias, weight loss and fever.
Initially diagnosed “seronegative SLE,” (she did not meet ARA criteria) and treated her with hydroxychloroquine. She improved somewhat.
Four years later, she developed non-bloody diarrhea, bloating, weight loss and night sweats. Eight months after that, she had an echo with an EF 30% and developed memory deficits and disorientation.
The combination of malabsorption with joint, CNS and heart involvement suggested Whipple’s disease.

47. The Moral of the Story: Not All Joint Pain Is Rheumatologic
The Moral of the Story: Not All Joint Pain Is Rheumatologic! DDx: rheum, infx, degenerative, trauma, iatrogenic...

48. Thanks for listening!