Pearls and Pitfalls of Rheumatologic Lab Investigations

Drs. Maysam Khalfan (biography, no disclosures) and Kam Shojania MD FRCPC (biography and disclosures) Disclosures: No conflict of interest. Has been involved with Augurex (a company that develops lab tests in rheumatology, and he is involved in a vasculitis clinical trial with UCB. Mitigating Potential Bias: Recommendations are consistent with current practice patterns and treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements.

What care gaps I have noticed

Patients who present with non-specific symptoms are sometimes tested with rheumatologic lab investigations as part of a ‘panel’ of tests. When these tests come back positive, it can lead to more confusion, patient anxiety, misdiagnosis or unnecessary referral. In general, clinical signs and symptoms will trump laboratory test results.  Below are a few tips on how to make the best use of common rheumatologic investigations, and if ordered, how to interpret results.

What I recommend – Practice tips (download as table)

1. Rheumatoid Factor (RF):

Pearls:

• The term ‘rheumatoid factor’ is a misnomer. RF positivity is seen in 5% of healthy individuals, and in a variety of non-rheumatologic conditions including Hepatitis C, HIV, subacute bacterial endocarditis, malignancy and cirrhosis¹. Most people with an elevated rheumatoid factor will not have rheumatoid arthritis (RA). Perhaps we should change the name of this test.
• RF testing is most useful in patients with a symmetric inflammatory polyarthritis, typically involving the MCP and PIP joints. Inflammatory features include prolonged morning stiffness (>1 hour), pain improving with activity, presence of joint swelling, and elevated CRP.

Pitfalls:

• A negative RF does not rule out rheumatoid arthritis in patients with an inflammatory symmetric polyarthritis. 30 to 50% of RA patients can be RF negative ^{2, 3}. Therefore, RF negativity should not prevent referral of a patient with inflammatory arthritis.

2. Anti-CCP antibodies:

Pearls:

• Anti-CCP is highly specific for rheumatoid arthritis (96% specificity, 57% sensitivity)^{4, 5}, and therefore when positive it is especially helpful in diagnosing RA.
• Anti-CCP is also a prognostic indicator. Anti-CCP positive RA patients are more likely to have joint destruction⁶ and extra-articular manifestations such as interstitial lung disease⁷.

Pitfalls:

• Out of pocket expense: Anti-CCP testing through primary care currently costs the patient $75 in BC. If you will be referring the patient to rheumatology then anti-CCP testing can be deferred because it is covered by MSP if ordered by rheumatology.  Moreover, many patients with rheumatoid arthritis will have a normal anti-CCP.

3. Anti-Nuclear Antibodies (ANA)

Pearls:

• ANA testing is most useful in patients who have specific connective tissue disease (CTD) features such as inflammatory arthritis, pleurisy or pericarditis, Raynaud’s phenomenon, interstitial lung disease, skin changes of scleroderma, rashes and cytopenias. ANA testing is not indicated to evaluate fatigue or musculoskeletal pain in the absence of other features suggestive of a CTD.  Lupus and other CTDs are primarily a clinical diagnosis.

Pitfalls:

• Fatigue and arthralgias are common complaints, while ANA positivity is also common in the general population (30% at 1:40 titre)⁸. Testing in patients with a low pre-test probability carries the risk of misdiagnosis, extraneous additional investigation and referral expenses⁹.

4. HLA B27

Pearls:

• Back pain is a very common complaint and 95% of HLA B27 positive people will NOT develop ankylosing spondylitis¹⁰, therefore testing HLA B27 in patients with back pain in general is not useful.
• HLA B27 testing is most useful when a patient has back pain with inflammatory features (age of onset < 40 years, pain improves with exercise, does not improve with rest). Suspicion for inflammatory back pain is increased in patients with a history of uveitis, inflammatory bowel disease, psoriasis or family history of ankylosing spondylitis.

Pitfalls:

• HLA B27 negativity does not rule out spondyloarthritis. Up to 10% of Caucasian patients with ankylosing spondylitis are HLA B27 negative¹¹. HLA-B27 negative spondyloarthritis is more common in non-Caucasian ethnic groups.

5. Serum Uric Acid:

Pearls:

• Target 360: When you are treating gout, aim to achieve serum uric acid level of less than 360 mmol/L for patients in whom uric acid lowering therapy is indicated (³2 gout attacks/year, presence of gouty tophi, renal calculi, or stage 2 CKD or worse)¹².
• Monthly serum uric acid testing is appropriate when initiating and titrating allopurinol dose. Once target is achieved, serum uric acid testing can be spaced out to every 6 months to ensure urate levels are within target.

Pitfalls:

• In a patient with suspected gout, a normal serum uric acid does not rule out gout. Serum uric acid can transiently become normal during gout flares and for a few weeks later¹³.
• As well, an elevated serum uric acid in a patient with acute monoarthritis does not confirm a diagnosis of gout.  Gout is best diagnosed by aspirating the joint and sending it for crystal analysis.  The joint aspiration can also look for septic arthritis – a worrisome possibility in acute monoarthritis.

6. HLA B5801

Pearls:

• Koreans, Han Chinese, Thai patients and patients of African background have higher than average frequency of HLA B5801 positivity, an HLA allele which confers a high risk of developing Allopurinol Hypersensitivity Syndrome (AHS). Therefore, consider testing for HLA B5801 in this group of patients prior to initiation of allopurinol, and if positive, allopurinol should be avoided¹².

Pitfalls:

• Adverse reactions to allopurinol can still occur in the absence of HLA B5801, and therefore allopurinol should be stopped if a patient experiences rashes, cytopenias, transaminitis or acute kidney injury.

7. Creatine Kinase (CK):

Pearls:

• From a rheumatologic perspective, testing CK level is useful in patients with proximal muscle weakness to assess for the presence of an inflammatory myositis. Pre-test probability is increased with additional features such as exposure to statins, a new unexplained rash, or a confirmed/suspected malignancy.
• CK elevation in inflammatory myositis is usually not subtle, and typically it is elevated in the range of 5 to 50 times the upper limit of normal and does not normalize with rest ¹⁴.

Pitfalls:

• Elevated CK in an asymptomatic patient? If the patient has been exercising, repeat the CK after 3 or more days without exercise or strenuous activity. Further investigation is not recommended in an asymptomatic patient unless CK level exceeds the 97.5^th percentile according to gender and race^{15, 16}, i.e:
  • >1001 IU/L in Black males, >487 IU/L in Black females
  • >520 IU/L in Asian males, >194 IU/L in Asian females
  • >382 IU/L in White males, >295 IU/L in White females

• A very high CK can also be seen after trauma, IM injections or very significant muscular exertion. It should improve within days without treatment.

8. ESR & CRP:

Pearls:

• It is rarely useful to order both ESR and CRP, and in British Columbia only CRP is payable when both ESR and CRP are ordered outside of the Emergency Department. CRP should be the preferred test because it is more specific for inflammatory conditions.

Pitfalls:

• ESR is not very specific for inflammation and can be elevated in many non-inflammatory states, including elderly age, anemia, malignancy and chronic kidney disease¹⁷.

(Download: Pearls and Pitfalls)

References:

1. Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: Clinical applications. Dis Markers. 2013;35(6):727–734. DOI: 10.1155/2013/726598. (View)
2. Nell V, Stamm T, Eberl G, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005;64(12):1731-1736. DOI: 10.1136/ard.2005.035691. (View)
3. Barra L, Pope J, Bessette L, Haraoui B, Bykerk V. Lack of seroconversion of rheumatoid factor and anti-cyclic citrullinated peptide in patients with early inflammatory arthritis: a systematic literature review. Rheumatology. 2011;50(2):311-316. DOI: 10.1093/rheumatology/keq190. (View with CPSBC or UBC)
4. Whiting PF, Smidt N, Strene JA, et al. Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis. Ann Intern Med. 2010;152(7):456-464. DOI: 10.7326/0003-4819-152-7-201004060-00010. (View with CPSBC or UBC)
5. Braschi E, Shojania K, Allan M. Anti-CCP: a truly helpful rheumatoid arthritis test? Can Fam Physician. 2016;62(3):234. (View)
6. Van der Helm-van Mil A, Verpoort K, Breedveld F, Toes R, Huizinga T. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther. 2005;7(5):949-958. DOI: 10.1186/ar1767. (Request with CPSBC or view with UBC)
7. Kelly CA, Saravanan V, Nisar M, et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics – a large multicentre UK study. Rheumatology. 2014;54(9):1676-1682. DOI: 10.1093/rheumatology/keu165. (Request with CPSBC or view with UBC)
8. Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis. 2014;73(1):17-23. DOI: 10.1136/annrheumdis-2013-203863. (Request with CPSBC or view with UBC)
9. Fritzler MJ. Choosing wisely: Review and commentary on anti-nuclear antibody (ANA) testing. Autoimmun Rev. 2016;15(3):272-280. DOI: 10.1016/j.autrev.2015.12.002. (View with CPSBC or UBC)
10. Haroon N. Does a positive HLA-B27 test increase your risk of mortality? J Rheumatol. 2015;42(4):559-560. DOI: 10.3899/jrheum.150017. (View with CPSBC or UBC)
11. Zochling J, Smith E. Seronegative spondyloarthritis. Best Pract Res Clin Rheumatol. 2010;24(6);747-756. DOI: 10.1016/j.berh.2011.02.002. (View with CPSBC or UBC)
12. Khanna D, FitzGerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic non-pharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431-1446. DOI: 10.1002/acr.21772. (View)
13. Logan J, Morrison E, McGill P. Serum uric acid in acute gout. Ann Rheum Dis. 1997;56(11):696-697. DOI: 101136/adr.56.11.696a. (View)
14. Dimachkie M, Barohn R, Amato A. Idiopathic inflammatory myopathies. Neurol Clin. 2014;32(3):595-628. DOI: 10.1016/j.ncl.2014.04.007. (View)
15. Moghadam-Kia S, Oddis C, Aggarwal R. Approach to asymptomatic creatine kinase elevation. Cleve Clin J Med. 2016;83(1):37-42. DOI: 10.3949/ccjm.83a.14120. (View)
16. George MD, McGill NK, Baker JF. Creatine kinase in the U.S population. Medicine (Baltimore). 2016;95(33):e4344. (View)
17. Bedell S, Bush B. Erythrocyte sedimentation rate. From folklore to facts. Am J Med. 1985;78(6):1001-1009. DOI: 10.1016/0002-9343(85)90224-4. (Request with CPSBC or view with UBC)

Resource:

BC Guideline: C-Reactive Protein and Erythrocyte Sedimentation Rate Testing guideline:  https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/esr

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Pearls and Pitfalls of Rheumatologic Lab Investigations

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