Laboratory Testing

Laboratory testing has been one of the cornerstones in the assessment of patients suspected of having RA. The most commonly used tests are the serum RF, ACPA, ESR, and CRP. RF and anti-CCP antibodies are helpful in the diagnosis of RA and in prognostication. The presence of these antibodies predicts which patients would be at high risk of functional decline and radiographic progression. They are also known to be positive in approximately half of RA patients, even before the onset of clinical disease with a median interval of 4.5 years.22 On the other hand, ESR and CRP are most helpful in estimating disease activity.

 

 

Figure 2. Patient with long-standing RA

Her left hand shows complications of rheumatoid arthritis such as ulnar deviation of the digits and intrinsic muscle wasting

Heilman, James, MD. Rheumatoid Arthritis. Digital image. Wikipedia, 07 Aug. 2010. Web. 22 May 2014.

 

Rheumatoid Factor. As measured in most laboratories, RFs are IgM autoantibodies directed against the Fc portion of immunoglobulin G (IgG). These are present in 75-80% of RA patients at some point during the course of the disease.23 The sensitivity of RF in RA is 69% and the specificity is 85%.24 The specificity is quite low, as it may be present in a variety of other diseases such as HCV, Sjogren’s syndrome, SLE, bacterial endocarditis, and tuberculosis among others.25

Anti-cyclic Citrullinated Peptides. Anti-CCP antibodies are detected through the ELISA method and have roughly the same sensitivity as RF at 67%. However, anti-CCP has the distinct advantage of having a higher specificity of 95%.24 Although specific, this antibody can also be found in other diseases such as SLE, Sjogren’s syndrome, and active tuberculosis. It should be noted, however, that anti-CCP positivity is rare in hepatitis C. This is in contrast to RF, which is fairly common in HCV infections. The combination of RF and anti-CCP positive tests increases the probability of true positives in the diagnosis of RA.26

Erythrocyte Sedimentation Rate. The ESR test has been used in a variety of settings; however, its utility lies mostly in following levels of inflammation. ESR values may correlate with disease activity in RA and thus have been incorporated in the Disease Activity Score 28 (DAS28) scoring instrument, which is used in approximating RA disease activity and is useful in monitoring patient response to medications. The pitfall of ESR, unfortunately, is that this test is nonspecific. Various factors such as age, hemoglobin level, renal function, and presence of infection affect the test values. Thus, care should be carried out in using this test.

C-reactive Protein. CRP is an acute phase reactant that is considered a sensitive indicator of inflammation. In low levels, it is present in atherosclerosis, diabetes mellitus, and obesity. In high levels, it may indicate bacterial infection or inflammation.1 In RA, this may be used in the same way as the ESR to approximate disease activity using the DAS28 instrument. However, caution is advised because up to 40% of RA patients at presentation have normal ESR or CRP.27

Table 3. American College of Rheumatology Recommendations on Use of Vaccines in RA Patients Starting or Currently Receiving DMARDs or Biologic Agents



Pneumococcal

Influenza (Intramuscular killed vaccine)



Hepatitis B


Human
Papillomavirus



Herpes Zoster

Combination DMARDs2

Anti-TNF biologics3

Recommended to be given prior to initiation of treatment.5

Non-TNF biologics4

Recommended to be given prior to initiation of treatment.5

DMARDs = disease-modifying antirheumatic drugs; = recommend vaccination when indicated (based on age and risk);
anti-TNF = anti-tumor necrosis factor.

1DMARDs examples: methotrexate, sulfasalazine, hydroxychloroquine, leflunamide among others.

2Combination DMARDs consists of combination of any of the above medications (usually methotrexate with another drug)

3Anti-TNF Biologics include adalimumab, certolizumab, etanercept, golimumab, infliximab

4Non-TNF Biologics include abatacept, rituximab, tocilizumab

5Live attenuated vaccines are not recommended to be given to patients already taking DMARDs or any biologic agent.

Adapted from Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639.

DMARD monotherapy1

 

Treatment

Several guiding principles should be followed in the treatment of patients with RA. The ACR and EULAR have published recommendations for the management of RA.28,29 The following recommendations help ensure that the patient is likely to have a good and safe outcome during the course of treatment

Early Diagnosis and Treatment of RA. As seen in comparative studies, treatment of RA is more effective in controlling disease if started earlier.1 This is especially important since avoiding functional decline and decreasing discomfort are major goals in treating RA. The treatment includes DMARDs, as they are able to modify the disease, as opposed to simply treating symptoms such as inflammation and pain.30 A treat-to-target (i.e., low disease state) strategy should be used in RA therapy. Broadly, DMARDs can be divided into synthetic/traditional and biologic.31

Synthetic DMARDs include methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. Methotrexate has been considered the anchor and first-line drug for the treatment of RA. The ACR recommends that patients with early RA (< 6 months) be started on DMARD monotherapy if they have low disease activity or if they do not have poor prognostic features (i.e., RF/CCP positivity, erosions on x-rays). However, if these factors are present, a combination of multiple DMARDs would then be recommended.27 Various combinations of synthetic DMARDs that include methotrexate have been found efficacious and safe. More recently, the so-called triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) was found to be possibly as effective as the combination of methotrexate and etanercept, a biologic DMARD.32

Biologic DMARDs include medications that target specific cytokines, receptors, or cell surface molecules in the pathophysiology of RA. They can be classified according to their mechanism of action: 1) tumor necrosis factor (TNF)-alpha inhibitors include the medications adalimumab, certolizumab pegol, etanercept, infliximab and golimumab; 2) the medication rituximab is a B-cell depleting monoclonal antibody that acts by targeting the CD20 cell surface molecule; 3) abatacept is a selective costimulation modulator targeting the the T-cell activation process; 4) anakinra is an interleukin-1 receptor antagonist; 5) tocilizumab is an interleukin-6 inhibitor; 6) tofacitinib, the most recently approved RA therapy, inhibits the Janus kinase pathway. These medications usually are given either through subcutaneous injection or via infusion (tofacitinib is the only oral agent). They are indicated for the treatment of RA either as monotherapy (except infliximab) or in combination with methotrexate. All of these medications have good efficacy and safety in the treatment of RA.

 

Table 4. ACR Recommendations on Laboratory Evaluation for Patients Receiving Biologic and Nonbiologic DMARDs


CBC

Liver Function Tests

Serum
Creatinine

Hepatitis B
and C Screen

Ophthalmologic Examination1

Leflunomides

Methotrexate

Sulfasalazine

All biologic agents

1Ophthalmologic examination is recommended within the first year of treatment. Annual follow up recommended for patients who are of higher risk (e.g., liver disease, concomitant retinal disease, and age ≥ 60 years)

Adapted from Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-784.

Hydroxychloroquine

 

Screening for tuberculosis, HBV, and HCV prior to treatment. Infections, especially tuberculosis, are increased in patients taking DMARDs.33 Thus, it is vital to screen for these diseases prior to treatment. The ACR recommends the tuberculin skin test or interferon-gamma release assay as the initial test in all RA patients starting biologic agents. If they are found to be positive, appropriate diagnosis and treatment for active or latent tuberculosis should then follow. Generally, biologic DMARDs can be used in patients with latent TB only if they are undergoing treatment and have done so for at least 1 month. The viral hepatitis status, whether positive or negative for active/chronic disease, should also be ascertained. Any biologic agent is not recommended for patients with untreated chronic hepatitis B, while etanercept may be used cautiously in patients with hepatitis C.27

Vaccination in patients starting or currently receiving DMARDs therapy. As DMARD agents can blunt response to vaccines, vaccination is recommended prior to receiving these medications. If they are already on DMARD therapy, several vaccines can also be given. Table 3 shows the recommendations from the ACR regarding vaccination in patients with RA.

Treatment goal is to reach remission or low disease activity. Treatment strategies should aim to prevent functional decline, improve comfort, and halt disease progression. These would be achieved only with tight control of disease activity. The rheumatologist should be the primary director of the RA patient’s care as the specialist would have the experience and knowledge necessary to evaluate and adjust the treatment regimen according to the patient’s needs. It is therefore recommended that patients be referred in a timely fashion to a rheumatologist, which allows for the diagnosis to be confirmed and an appropriate plan of care started. The primary care physician also plays a pivotal role and should share in the management of RA.34

Close monitoring for adverse effects of drug therapy. As with any other medications, the physician should observe for potential adverse effects or toxicity associated with DMARD therapy. Abnormalities in liver and renal function as well as bone marrow suppression can occur during DMARDs therapy. Table 4 shows the ACR recommendations regarding monitoring the side effects of these drugs.35

Approach to the Diagnosis of RA

Rheumatoid arthritis should be suspected in any patient presenting with swollen and/or tender joints (i.e., polyarthritis). A thorough history is important, with special focus on the number and location of joint pains and swelling, as well as the presence of morning stiffness and other associated symptoms. Medication history is obtained for use of analgesics, corticosteroids, or nonsteroidal anti-inflammatory agents and their effects on joint complaints. A personal history for the presence of symptoms compatible with psoriasis, spondyloarhtropathies, inflammatory bowel disease, and SLE is also sought. Infections or risk for infections such as HIV, hepatitis, or other acute viral illnesses are assessed during the visit as well.

Physical examination focusing on the joints is necessary to assess for any synovitis, joint limitation of motion, or any deformities. A quick search for any skin lesions (psoriatic rashes, malar or discoid rashes), rheumatoid nodules, or gout tophi is included in the examination.

Laboratory testing to support the history and physical examination includes complete basic chemistries, complete blood count, as well as ESR, CRP, RF, and anti-CCP. Other evaluations that would also be considered are hepatitis screen (HBsAg, anti-HBc, anti-HCV) and testing for latent tuberculosis infection (Tuberculin skin test or any of the Interferon-Gamma Release Assays- Quantiferon-TB Gold test or T-Spot test). The latter tests would be helpful in ruling out conditions that potentially may cause contraindications to any potential treatments such as DMARDs.

Radiographic imaging of all the major joints is obtained. This will assess for any damage to the joints caused by the inflammation as well as serve as a baseline for disease monitoring. The radiographs will also be helpful in differentiating other forms of inflammatory arthropathies, such as psoriatic arthritis and crystal arthritis among others, as the changes found on these conditions are usually distinct from RA.

Other imaging modalities are also available to aid in the diagnosis of rheumatoid arthritis. Magnetic resonance imaging and musculoskeletal ultrasound of the affected joints can be used to detect subtle inflammatory changes. These modalities are found to be more sensitive than radiographs in detecting synovitis. These tests are becoming more available in many rheumatology offices and may be used to detect synovitis not seen on clinical exam.36

Risk factor assessment and counseling is also done during the visit. The most significant modifiable risk factor for development of RA is smoking. Education on the importance of smoking cessation is given to the patient. If they are considering cessation, appropriate referrals are provided. If the patient is obese or has metabolic syndrome, counseling on addressing these will also be included since obesity is a risk factor for poor remission rates in patients with longstanding RA treated with anti-TNF agents.37

Conclusion

Rheumatoid arthritis is a polyarticular inflammatory arthritis that demands early diagnosis and treatment for improved patient outcomes.

References

1. Lard LR, Visser H, Speyer I, et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: Comparison of two cohorts who received different treatment strategies. Am J Med 2001; 111:446-451.

2. Cross M, Smith E, Hoy D, et al. The global burden of rheumatoid arthritis: Estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014;73:1323-1330.

3. Silman AJ, Hochberg MC. Epidemiology of the Rheumatic Diseases. 2nd ed. New York: Oxford University Press; 2001.

4. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum 2010;62:1576-1582.

5. Schur P, Gabriel S, Crowson, C. Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Accessed March 25, 2014..

6. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58:15-25.

7. Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol 2010;22:293-298.

8. Di Giuseppe D, Discacciati A, Orsini N, Wolk A. Cigarette smoking and risk of rheumatoid arthritis: A dose-response meta-analysis. Arthritis Res Ther 2014;16:R61.

9. Mercado F, Marshall RI, Klestov AC, Bartold PM. Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol 2000;27:267-272.

10. Rosenstein ED, Weissmann G, Greenwald RA. Porphyromonas gingivalis, periodontitis and rheumatoid arthritis. Med Hypotheses 2009;73:457-458.

11. Li X, Sundquist J, Sundquist K. Socioeconomic and occupational risk factors for rheumatoid arthritis: A nationwide study based on hospitalizations in Sweden. J Rheumatol 2008;35:986-991.

12. Stolt P, et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis 2010;69:1072-1076.

13. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:903-911.

14. Aletaha D, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-2581.

15. Edwards, MS. Rubella. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Accessed March 24, 2014.

16. Epidemiology and Prevention of Vaccine-Preventable Diseases. Centers for Disease Control and Prevention, 07 May 2012. Available at: www.cdc.gov/vaccines/pubs/pinkbook/rubella.html. Accessed March 24, 2014.

17. About Parvovirus B19. Centers for Disease Control and Prevention, 14 Feb. 2012. Available at: www.cdc.gov/parvovirusB19/about-parvovirus.html. Accessed March 24, 2014.

18. Colmegna I, Alberts-Grill N. Parvovirus B19: Its role in chronic arthritis. Rheum Dis Clin North Am 2009;35:95-110.

19. Han SH. Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis 2004;8:403-418.

20. Kemmer NM, Sherman KE. Hepatitis C-related arthropathy: Diagnostic and treatment considerations. J Musculoskelet Med 2010;27:351-354.

21. Olivieri I, Padula A, D’Angelo S, Cutro MS. Psoriatic arthritis sine psoriasis. J Rheumatol Suppl 2009;83:28-29.

22. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum 2004;50:380-386.

23. Taylor PC, Maini RN. Clinically useful biologic markers in the diagnosis and assessment of outcome in rheumatoid arthritis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Accessed on March 31, 2014.

24. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: Diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 2007;146:797-808.

25. Dörner T, Egerer K, Feist E, Burmester GR. Rheumatoid factor revisited. Curr Opin Rheumatol 2004;16:246-253.

26. Sun J, Zhang Y, Liu L, Liu G. Diagnostic accuracy of combined tests of anti cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: A meta-analysis. Clin Exp Rheumatol 2014;32:11-21.

27. Wolfe F, Michaud K. The clinical and research significance of the erythrocyte sedimentation rate. J Rheumatol 1994;21:1227-1237.

28. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625-639.

29. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492-509.

30. DMARD. Available at: www.dorlands.com. Accessed April 3, 2014.

31. Smolen JS, van der Heijde D, Machold KP, et al. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis 2014;73:3-5.

32. O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013;369:307-318.

33. Brassard P, Kezouh A, Suissa S. Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis 2006;43:717-722.

34. Rat AC, Henegariu V, Boissier MC. Do primary care physicians have a place in the management of rheumatoid arthritis? Joint Bone Spine 2004;71:190-197.

35. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-784.

36. Cyteval C. Doppler ultrasonography and dynamic magnetic resonance imaging for assessment of synovitis in the hand and wrist of patients with rheumatoid arthritis. Semin Musculoskelet Radiol 2009;13:66-73.

37. Gremese E, Carletto A, Padovan M, et al. Obesity and reduction of the response rate to anti-tumor necrosis factor alpha in rheumatoid arthritis: An approach to a personalized medicine. Arthritis Care Res (Hoboken). 2013;65:94-100.