RHEUMATOIDARTHRITIS

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Rheumatoid arthritisRheumatoid arthritis (RA) affects an estimated 1.5 million people in the United States.1 RA is the most common type of autoimmune arthritis. Treatments have improved greatly and help many of those affected. For most people with RA, early diagnosis and treatment can control joint pain and swelling, and lessen joint damage. LabCorp offers a variety of tests to aid in diagnosis, management of treatment and monitoring of disease activity.

RA DiagnosisTreatment

DecisionPre-Treatment

Testing

MonitorDisease Activity

Treatment Monitoring

BaselineDisease Activity

Physical Exam

Vectra DA(Monitor)

Thiopurine Metabolites

MTX Polyglutamates

Biologic Drug Concentration and Antibody Testing(DoseASSURE™)

RA Speci�cRheumatoid FactorAnti-CCP 3.114-3-3

In�ammationC-Reactive ProteinSed Rate

Rule OutAnti-Nuclear Abs

Optimize Treatmentor Lack of response

Physical Exam

Vectra DA(Baseline)

TreatmentManagement

Quantify active drug levels

Identify immunogenicity

Adjust dosing and frequency

Consider co-therapy

Switch Treatment

Biologic

Thiopurine

Methotrexate

CBC, Metabolic Panel,QuantiFERON Gold TB, Hepatitis B Screening

CBC, TPMT Enzymes, and/or TPMT Genetics

CBCMetabolic Panel

Non-ResponderSwitch treatment Add co-therapy

ResponderMonitor progress

Adjust dosing if indicated

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RA DiagnosisTreatment

DecisionPre-Treatment

Testing

MonitorDisease Activity

Treatment Monitoring

BaselineDisease Activity

Physical Exam

Vectra DA(Monitor)

Thiopurine Metabolites

MTX Polyglutamates

Biologic Drug Concentration and Antibody Testing(DoseASSURE™)

RA Speci�cRheumatoid FactorAnti-CCP 3.114-3-3

In�ammationC-Reactive ProteinSed Rate

Rule OutAnti-Nuclear Abs

Optimize Treatmentor Lack of response

Physical Exam

Vectra DA(Baseline)

TreatmentManagement

Quantify active drug levels

Identify immunogenicity

Adjust dosing and frequency

Consider co-therapy

Switch Treatment

Biologic

Thiopurine

Methotrexate

CBC, Metabolic Panel,QuantiFERON Gold TB, Hepatitis B Screening

CBC, TPMT Enzymes, and/or TPMT Genetics

CBCMetabolic Panel

Non-ResponderSwitch treatment

Add co-therapy

ResponderMonitor progress

Adjust dosing if indicated

Single-Source Solution for the Rheumatology SpecialistLabCorp offers a comprehensive testing menu and numerous service

benefits to support the needs of a rheumatology practice:

• Broad capabilities in autoimmune testing

• Specialized assays for treatment monitoring

• Multiple connectivity options

• More than 1900 patient service centers nationwide

• Extensive network of managed care health plans

• Experienced medical affairs professionals are available for consultation and educational programs

• LabCorp offers a dedicated hotline for biologic drug monitoring• Biologic Monitoring Hotline: 844-225-8877

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Test Name Test NoRheumAssureProfile includes:* Anti-CCP 3.1, Rheumatoid Arthritis (RA) Factor and 14.3.3 eta

504509

Rheumatoid Arthritis (RA) ProfileProfile includes:* Anti-CCP 3.1, Rheumatoid Arthritis (RA) Factor

164065

*Individual components may be ordered separately.

RA DiagnosisEarly diagnosis of RA is important because it has been recognized that early initiation of disease-suppressing therapy may improve clinical outcomes and reduce the accrual of joint damage and disability.2 LabCorp offers three RA-specific markers that, when used in combination, provide industry leading sensitivity as well as early diagnosis of RA.

Anti-CCP 3.1• LabCorp’s Anti-CCP 3.1 offers greater sensitivity than earlier CCP tests3

• Enhanced sensitivity is achieved by utilizing both IgG and IgA antibodies4 • Anti-CCP 3.1 provides a sensitivity of 70.3% and specificity of 97.8%4

• Anti-CCP 3.1, when used in combination with RF, provides greater sensitivity than RF alone5

• Anti-CCP 3.1 has been shown to correctly identify 83% of RA patients who were found to be RF negative3

• Anti-CCP 3.1 is the first assay approved for early detection of RA• Improved detection within 2 years of onset4

14-3-3 eta• The 14-3-3 eta protein is a joint-derived, proinflammatory mediator that is implicated in the joint erosion process and

pathogenesis of RA.6 • Positive serum 14-3-3 eta levels are associated with higher rates of joint damage as measured by radiographic

assessments using the Sharp/van der Heijde Score.6,7 • Serum testing shows that 14-3-3 eta is elevated in both early and established RA.6

• 14-3-3 eta is highly specific for RA. Serum 14-3-3 eta may be especially helpful in identifying patients with early RA, as it provides a 15% incremental benefit to the diagnostic sensitivity of markers including, Rheumatoid Arthritis (RA) Factor and Cyclic Citrullinated Peptide (CCP) Antibodies.7 • A higher level of 14-3-3ŋ also helps to identify RA patients who are most likely to exhibit rapid progression and need

earlier, tailored therapy.7

ProfilesLabCorp offers the following profiles to aid in the diagnosis of RA.

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RA Disease ActivityLaboratory testing is available to aid in the assessment of disease activity.

Crescendo Bioscience’s test, Vectra® DA (Test no. 819290), is available for ordering through LabCorp. Vectra DA assesses disease activity in adult rheumatoid arthritis (RA) patients. It provides a score, ranging from 1 to 100, that assesses RA disease activity, and is used to categorize the activity as low, moderate or high. This quantitative method can be used over time to track the progression of disease activity within RA patients. No kits are necessary for this test. Vectra DA is available for physicians to order through the standard LabCorp ordering process and collection can take place at LabCorp patient service centers. Additionally, reports will be delivered through the standard results delivery process for LabCorp.

Please note that LabCorp contracts do not apply as Crescendo Bioscience will continue to perform testing and billing for Vectra DA.

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Monitoring Methotrexate The reaction to methotrexate can vary widely among rheumatoid arthritis patients.8 Data suggests that the process of MTX polyglutamation is a function of the dosage level and administration method.8,9 It has been found that 30% to 40% of rheumatoid arthritis patients do not adequately respond to methotrexate treatment.10 A test indicating whether or not a patient has achieved an expected therapeutic level on a specific dosage can be useful in ongoing patient management.

Methotrexate Polyglutamates (MTXpgsRA) Test• It is considered important to work to attain dose optimization when treating patients on methotrexate.11

• Testing may be ordered at any time during therapy and should be conducted at least 36 hours after last dose of methotrexate.• The report for MTXpgsRA provides the measurement of each polyglutamate (1-5) and shares detailed information that can assist in

result interpretation and treatment planning.

Thiopurine-related TestingThiopurine related testing, including genetic and metabolic activity, may be used to identify patients who may be at risk for drug toxicity and to assess dosage, and to maximize treatment effectiveness.12

TPMT Activity Test and TPMT Genetic TestDue to potential toxicity that can occur even with standard Thiopurine dosages in patient with TPMT enzyme deficiency, the FDA-approved label recommends consideration for testing for the common TPMT gene mutations (genotype) or TPMT activity (phenotype) before beginning treatment.13

TPMT Enzyme Activity Test• Utilize prior to treatment as a screen for low TPMT activity• Interpretive reports support initial dosing decisions• TPMT Activity directly measures red blood cell thiopurine S-methyltransferase activity and may detect clinically relevant

mutations not detected in the TPMT Genetic Test

TPMT Genotyping• TPMT genetic testing has a clinical sensitivity of approximately 95% for TPMT mutations # *2, *3A, *3B, and *3C14 and is not

sensitive to red blood cell transfusion or environmental factors that can impact results for TPMT Activity

Thiopurine Metabolites Test• Utilize during treatment to help reach and maintain therapeutic goal12

• Assists with evaluating unresponsive patients12

• Monitors responsive patients to avoid potential toxicity12

• Drug concentrations reported for 6-TG (6-thioguanine) and 6-MMP (6-methylmercaptopurine)

RA Treatment MonitoringAlthough RA treatment is multifaceted, medications play an important role in patient management. Newly developed laboratory assays aid physicians in monitoring use and maximizing effectiveness of both disease-modifying anti-rheumatic drugs (DMARDs) and biologics.1

Drug Name Test Name Test No DescriptionRasuvoRheumatrexDosepakTrexall

MethotrexatePolyglutamates

504104 MTXpgsRA measures the total MTXPGs and reports each species (1-5) of polyglutamates, which can help clinical management by assuring that an individual patient is receiving an adequate dose to expect a clinical response and rule-out noncompliance.

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Monitoring Biologics — Therapeutic drug monitoring for biologics is a valuable tool to evaluate dose and tailor dose adjustments to your individual patient.15-19 Dosing by weight and empiric dose adjustment may be inefficient and suboptimal.16,19 DoseASSURE™, LabCorp's portfolio of biologics monitoring assays, may help physicians optimize biological therapy using a personalized, patient-specific approach by:• Aiding in titrating doses and adjusting frequency to maximize effectiveness15,16

• Help differentiate non-compliance and under-treatment from other causes of lack of response.17

• Assisting in preventing and managing loss of response due to immunogenicity15,18

• Minimizing cost to patient by avoiding unhelpful dose escalation19

• Predicting which patients are likely to retain long-term response20

Clinical efficacy in RA has been shown to correspond with serum concentrations of adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and ustekinumab.18,21-25,36

Immunogenicity Testing (Anti-drug Antibody Level)• As many as one third of RA patients on biological therapy may develop anti-drug antibodies.29,30• Anti-drug antibodies can adversely affect the amount of drug in the body.15,29-31• Co-therapy with methotrexate, sufficient drug levels, and maintenance dosing (vs. episodic or on-demand use) reduce the risk of

anti-drug antibody formation.29-34

Drug Normal half-life Proposed Target Ranges for Trough Concentrations§

Other clinical data on Trough Concentrations

Adalimumab Approx. 2 weeks 5 - 8 ug/mL in RA22; 5 - 8 mg/L in PA26; 3.5 – 7.0 mg/L in psoriasis27

Certolizumab Approx. 2 weeks >23 µg/mL corresponded to better EULAR response rates.36

A definitive target range has yet to be determined.

Etanercept 3 – 5.5 days > 3.1 ug/mL (at 3 months predicted response at 6 months in RA.)28

In RA, good responders had higher levels (median 3.8 mg/L, 2.5 – 5.2) compared to non-responders (2.8 mg/L, 1.3 -3.9).23 In AS, clinical responders (ASDAS) had higher median levels (median 3.8 mg/L, 2.5 – 5.2) than non-responders (2.3 mg/L, 1.2 – 3.4).20

Golimumab Approx. 2 weeks No consensus on clinical recommendation for RA

In RA, higher levels (median 3.4 ug/mL) were associated with a greater rate of clinical response (ACR20).24

Infliximab 7.7 to 9.5 days < 2 ug/mL: low and ≥ 8 ug/mL: high in RA16

In RA, responders had higher levels (median 3.6 mg/L, 1.4 – 8.2) than non-responders (0.5 mg/L, 0.2 – 2.2).21

Rituximab 18 days (5.2-77.5 days)

No consensus on clinical recommendation for RA

Ustekinumab Approx. 3 weeks A definitive target range has yet to be determined

In psoriasis, PASI 50 responders had higher trough concentrations than non-responders.35

§Note: These targets concentrations were those used in landmark studies and do not necessarily translate into general recommendations for individual patients. Please see referenced literature for more details.

Treatment ManagementLabCorp’s variety of test options provide physicians information that may assist in treatment management decisions.

Treatment decisions based on quantification of active drug levels, and the identification of immunogenicity can assist physicians with the following decisions:• Adjustment of dose and frequency• Consideration of co-therapy• Treatment change based on patient response

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References1. Handout on Health: Rheumatoid Arthritis. National Institute of Arthritis and Musculoskeletal and Skin Diseases Website http://www.niams.nih.gov/health_info/Rheumatic_Disease/default.asp#ra_2 . Accessed February 25, 2014.2. Aletha D, Neogi T, Silman AJ. 2010 rheumatoid arthritis classification criteria. Arthritis Rheum. 2010;62(9):2569-2581.3. Szabo Z, Soós L, Lakos G, Sipka S, Szekanecz. Performance of third generation anti-CCP assays. Poster presented at: Controversies in Rheumatology and Autoimmunity (CDRA); March 10-12, 2011; Florence, Italy.4. QUANTA Lite™ CCP 3.1 IgG/IgA ELISA [directional insert]. INOVA Diagnostics, Inc; October 2009. Revision 2.5. Vallbracht I, Rieber J, Oppermann M, Förger F, Siebert U, Helmke K. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis. 2004;63:1079-1084.6. Maksymowych WP, van der Heijde D, Allaart CF, Landewe R, Boire G, Tak PP, et al. 14-3-3eta is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage Arthritis Res. Ther., 16 (2014), p. R99.7. Carrier N, Marotta M, de Brum-Fernandes A, Liang P, Masetto A, Menard HA, et al. Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis. Arthritis Research & Therapy. 2016; 18(37) 1-14.8. Dervieux T, Zablocki R, Kremer J. Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology (Oxford). 2010 Dec; 49(12):2337-2345.9. Danila MI, Hughes LB, Brown EE, et al. Measurement of erythrocyte methotrexate polyglutamate levels: ready for clinical use in rheumatoid arthritis? NIH Public Access.2010;12(5):342-347.10. Goodman S. Measuring methotrexate polyglutamates. Clin Exp Rheumatol. 2010 Sep-Oct; 28 (5 Suppl 61): S24-S26.11. Smolen JS, Landewe 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;73:492-509.12. Chevaux JB, Peyrin-Biroulet L, Sparrow MP. Optimizing thiopurine therapy in inflammatory bowel disease. Inflamm Bowel Dis. 2011 Jun; 17(6): 1428-1435.13. IMURAN® (azathioprine) [package insert]. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016324s034s035lbl.pdf. Accessed: January 27, 2016.14. Yates CR, Krynetski EY, Loennechen T, et all. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997 Apr 15; 126(8):608-614.15. Vincent FB, et al. Antidrug antibodies to tumour necrosis factor (TNF)-specific neutralizing agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013;72:165-178.16. Mulleman D, et al. Infliximab concentration monitoring improves the control of disease activity in rheumatoid arthritis. Arthritis Res Therapy 2009;11(6):R178.17. Chen DY, et al. Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis. Ann Rheum Dis 2015;74:e16.

18. Mulleman D, et al. Should anti-TNF-a drug levels and/or anti-drug antibodies be assayed in patients treated for rheumatoid arthritis? Joint Bone Spine 2012;79:109-112.19. Krieckaert CLM, et al. Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects. Ann Rheum Dis 2015;74:361-368.20. Kneepkens EL, et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 2015;74:1825-1829.21. Wolbink GJ, et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:704-707.22. Pouw MF, et al. Key finding towards optimizing adalimumab treatment:the concentration-effect curve. Ann Rheum Dis 2015;74:513-518.23. Jamnitski A, et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann Rheum Dis 2012;71:88-91.24. Kay J, et al. Golimumab in Patients with Active Rheumatoid Arthritis Despite Treatment with Methotrexate. Arthritis Rheum 2008;58(4):964-975.25. Diana M, et al. Correlation between serum rituximab level and clinical response in rheumatoid arthritis patients treated with a B cell depletion therapy. Ann Rheum Dis 2014;73:390.26. Vogelzang E, et al. A concentration-effect curve of adalimumab in patients with psoriatic arthritis. Ann Rheum Dis 2014;74:88-89.27. Menting SP, et al. Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis. JAMA Derm 2015;151(6):616-622.28. Daien CI, et al. Etanercept Concentration in Patients with Rheumatoid Arthritis and Its Potential Influence on Treatment Decisions: A Pilot Study. J Rheumatol 2012;39:1533-1538.29. Schaeverbeke T, et al. Immunogenicity of biologic agents in rheumatoid arthritis patients: lessons for clinical practice. Rheumatol 2016;55:210-220.30. Pascual-Salcedo D, Et al. Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatol 2011;50:1445-1452.31. Bartelds GM, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007;66:921-926.32. Thomas SS, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs. 2015;29:241-258.33. Garces S, et al. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis 2013;72:1947-1955.34. Krieckaert CL, et al. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012;71(11):1914-1915.35. Chiu H-Y, Chu TW, Cheng Y-P, Tsai T-F. The association between clinical response to ustekinumab and immunogenicity to ustekinumab and prior adalimumab. PLoS One. 2015;10(11):e0142930. doi: 10.1371/journal.pone.0142930.36. Jani M et al. High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort Ann Rheum Dis 2017;76:208-213.ext.

Rheumatoid Arthritis and Related TestingTest Name Test No. 14-3-3 eta, Rheumatoid Arthritis 504550Adalimumab and Anti-Adalimumab Antibody (Serial Monitor), DoseASSURE™ ADL 503890Certolizumab and Anti-Certolizumab Antibody, DoseASSURE™ CTZ 504627Cyclic Citrullinated Peptide (CCP) Antibodies, IgA, IgG, ELISA 164914Etanercept and Anti-Etanercept Antibody (Serial Monitor), DoseASSURE™ ETN 504245Golimumab and Anti-Golimumab Antibody, DoseASSURE™ GOL 504563Infliximab and Anti-Infliximab Antibody (Serial Monitor), DoseASSURE™ IFX 503870Methotrexate polyglutamates 504104RheumAssure 504509Rheumatoid Arthritis (RA) Factor 006502Rheumatoid Arthritis (RA) Profile 164065Rituximab and Anti-Rituximab Antibody, DoseASSURE™ RTX 504355Thiopurine Metabolites 503800Thiopurine Methyltransferase (TPMT), Enzyme Activity, Erythrocytes 510750Thiopurine Methyltransferase (TPMT) Genotyping 504142Ustekinumab and Anti-Ustekinumab Antibody, DoseASSURE™ UST 504594

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