RHEUMATOLOGY NURSE NEWSLETTER

Transcription

1 To claim CE credits after reading this issue of Rheumatology Nurse, go to ranews RHEUMATOLOGY NURSE NEWSLETTER Educational Planning Committee Kori A. Dewing, DNP, ARNP Adult Nurse Practitioner Virginia Mason Medical Center Seattle, Washington Jacqueline Fritz, RN, MSN, CNS ISSUE 4 of VOLUME 6 Release Date: December 15, 2013 Expiration Date: December 15, 2015 Inside This Issue Critical Care and Rheumatology Specialist Medical Advancement Center Cypress, California Why are anti-citrullinated peptide antibodies (ACPAs) seen today as being more predictive of likely rheumatoid arthritis (RA) than rheumatoid factor (RF)? Joyce M. Kortan, RN How does ACPA-positive RA differ from ACPA-negative RA? Infusion Nurse Park Nicollet Health Services St. Louis Park, Minnesota Vicky Ruffing, RN Nurse Manager Johns Hopkins Arthritis Center Johns Hopkins University Baltimore, Maryland Where do we stand in being able to distinguish between patients who are more or less likely to respond to tumor necrosis factor (TNF) inhibitors? Where do we stand in being able to distinguish between patients who are more or less likely to respond to methotrexate (MTX)? Rheumatology Nurse Newsletter: Issue 4 of Volume 6 1

2 2 LEARNING OBJECTIVES 1. Identify biomarkers used in the current American College of Rheumatology classification criteria for the diagnosis of RA, as well as those used in prognostic guidelines 2. Identify the most common genetic markers present among patients diagnosed with RA 3. Determine the role, if any, disease activity assays should play in your practice 4. Discuss ways in which the development of antidrug antibodies can be reduced among patients taking anti-tnf therapy DISCLOSURE It is the policy of the Institute for Continuing Healthcare Education (the Institute) that the education presented within Institute-provided, CNE-certified activities be unbiased and based upon scientific evidence. To help participants make judgments about the presence of bias, the Institute provides information that planners, teachers, authors, developers, and activity managers have disclosed about financial relationships they have with commercial entities that produce or market products or services related to the content of this educational activity. Any relationships that an individual may have with commercial entities have been disclosed and reviewed, and any potential conflicts have been resolved. Relationships are abbreviated as follows: E, Educational planning committee; G, Grant/research support recipient; A, Advisor/review panel member; C, Consultant; S, Stock shareholder; SB, Speaker bureau; PE, Promotional event talks; H, Honoraria; O, Other. Kori A. Dewing, DNP, ARNP, has disclosed that she does not have any relevant financial relationships specific to the subject matter of the content of the activity. Jacqueline Fritz, RN, MSN, CNS, has disclosed the following relevant financial relationships that have occurred within the past 12 months: UCB/A,PE,SB; Genentech, AbbVie, Pfizer, Savient/PE, SB. Joyce M. Kortan, RN, has disclosed the following relevant financial relationships that have occurred within the past 12 months: UCB, Janssen/A,PE,SB; Amgen/Pfizer, Savient, Genentech/PE,SB. Vicky Ruffing, RN, has disclosed that she does not have any relevant financial relationships specific to the subject matter of the content of the activity. ACCREDITATION STATEMENT The Institute for Continuing Healthcare Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. This activity offers 1.5 contact hours to participating nurses. This credit may be applied toward licensure requirements in those states that recognize American Nurses Credentialing Center s Commission on Accreditation (ANCC-COA) accredited providers. Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA. The Institute for Continuing Healthcare Education is approved by the California Board of Registered Nursing, Provider Number The Institute for Continuing Healthcare Education approves this activity for 1.8 contact hours. Jacqueline Fritz, RN, MSN, CNS, is the nurse planner for this activity. TARGET AUDIENCE The intended audience for this activity includes rheumatology nurses, rheumatology advanced practice nurses, and infusion nurses. CONTENT FREELANCER Anne Jacobson, MPH, CCMEP, Medical Writer, has disclosed that she does not have any relevant financial relationships specific to the subject matter of the content of the activity. CONTENT PEER REVIEWER This newsletter was reviewed by Sheree C. Carter, RN, MSN, CNS. Ms. Carter has disclosed that she does not have any relevant financial relationships specific to the subject matter of the content included in this educational activity. ACTIVITY DEVELOPMENT AND MANAGEMENT TEAM Cathy Pagano, CCMEP; Sandra Davidson; Allison Muller, PharmD, D.ABAT; Scott Kober, MBA, CCMEP; and Megan Small, are employees of the Institute and are collectively responsible for the planning, development, and management of this CNE activity. These individuals have disclosed that they have had no relevant financial relationship specific to the subject matter of this activity that have occurred within the past 12 months. PRODUCT DISCLOSURE This educational activity includes discussion of published and/or investigational uses of agents that are not indicated by the U.S. Food and Drug Administration. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. The educational content of this activity has been peer reviewed and validated to ensure that it is a fair and balanced representation of the topic, based on the best available evidence. To claim CE credits after reading this issue of Rheumatology Nurse, go to

3 PERSONALIZED MEDICINE IN RHEUMATOLOGY: THE NURSING PERSPECTIVE Rheumatoid arthritis (RA) is a heterogenous disease that cannot be managed effectively with a one-size-fits-all approach. 1 In patients with RA, the presence of rheumatoid factor (RF) is a biological red flag that signals aggressive disease and poor prognosis. RF is an example of a biomarker, a measurable biologic parameter that provides information about an underlying disease state. Biomarkers allow clinicians to make well-informed, scientifically sound treatment decisions based on objective disease measures. Biomarkers have revolutionized patient care in many practice settings. For example, hemoglobin A1c (HbA1c) is a marker of glucose metabolism that is used to monitor response to antidiabetic agents and guide treatment decisions. 2 In the management of patients with breast cancer, clinicians use biomarker tests such as Oncotype DX and MammaPrint to understand the risk of recurrence and predict the likelihood of response to chemotherapy. 2 Rheumatology providers have seen biomarkers play an increasingly prominent role in RA diagnosis over the past few decades. In the 1987 American College of Rheumatology (ACR) classification criteria, a positive test for RF was 1 of 7 features that could count towards a diagnosis of RA (a total of any 4 were required). 3 Under the current classification criteria, positive laboratory tests for RF or anti-citrullinated peptide antibodies (ACPA), as well as abnormal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels, can all contribute to the total points needed to classify a patient as having RA. 4 In the ACR treatment guidelines, the presence of RF and ACPA are considered features of poor prognosis that necessitate a more aggressive course of therapy. 5 Changes to the RA classification criteria illustrate how much biomarkers have already contributed to RA management, and yet also how much farther there is to go. Current biomarkers are valuable in supporting the diagnosis of RA for most patients, yet there are many situations where biomarkers are not helpful. At least 1 in 6 patients with early RA have normal test results for RF, CRP, and ESR (see Figure 1). 6 Patients with normal laboratory tests may be less likely to be referred to a rheumatologist, leading to delayed diagnosis and treatment. 6 Once clinicians diagnose RA and confirm RF and ACPA status, biomarkers currently have a limited role in current RA management. Recent research, however, may be poised to introduce personalized medicine into multiple stages of RA management (see Table 1 on page 4). Biomarkers have the potential to refine current RA care through earlier diagnosis, better prediction of disease severity, individualized treatment selection, and detailed monitoring of therapeutic response. 1 This issue of Rheumatology Nurse summarizes the current and future applications of biomarkers in RA management. The 3 sections will focus on the following: 1. Biomarkers used to diagnose RA and predict aggressive disease 2. Biomarkers used to assess RA disease activity and gauge treatment response 3. Biologic markers that are formed in the presence of specific RA treatments, including methotrexate (MTX) and antitumor necrosis factor (TNF) agents Figure 1: Laboratory Findings in Patients with Newly Diagnosed RA 70% 60% 62% 54% 56% Normal Abnormal 50% 45% 44% 40% 38% 30% 28% 20% 15% 10% 0% RF ESR CRP Negative RF, normal ESR, AND normal CRP Positive RF, abnormal ESR, AND abnormal CRP CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor. Source: Sokka T, Pincus T. Erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor are normal at presentation in 35%-45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol. 2009;36: Rheumatology Nurse Newsletter: Issue 4 of Volume 6 3

4 DIAGNOSTIC MARKERS IN RA Rheumatoid Factor RF is a nonspecific marker of RA that is eventually present in up to 80% of RA patients. 3 The presence of RF in early RA is associated with more severe disease activity, but RF becomes less predictive as the disease progresses. 7 In the future, testing for RF may help to identify individuals who are at an increased risk of developing RA. In a recent Danish study, researchers measured RF levels in 9,712 adults who had no RA symptoms at the start of the study and followed them for up to 28 years. 8 Patients were divided into 4 groups based on baseline plasma RF levels: <25 IU/mL IU/mL IU/mL >100 IU/mL The risk for development of RA increased significantly with each group. Compared with patients with a baseline RF level of <25 IU/mL, the risk of developing RA was 3.3 times higher in the 25-to-50 IU/mL group, 6.0 times higher for the 50.1-to-100 IU/mL group, and 26 times higher for the greater than 100 IU/mL group. The researchers also examined other factors that influence the long-term risk of RA, such as age and smoking status. The subgroup with the highest risk for RA was women aged 50 to 69 years of age who smoked and had RF levels 100 IU/mL at study entry. For these women, the 10-year risk of developing RA was 32%. 8 According to the study authors, these findings support early referral to a rheumatology specialist for patients who have a positive RF test ( 25 IU/mL in this study), even in the absence of typical RA symptoms. 8 In current practice, screening for RF in the general population is considered impractical, given how many millions of tests would be needed to identify presymptomatic RA. However, experts remain hopeful that biomarkers will be the key to identifying RA very early in the disease course, when treatment has the best chance of improving long-term prognosis. 9 Future studies may assess whether it is worthwhile to measure RF in certain asymptomatic individuals, such as those with a strong family history of RA. Table 1: Potential Uses for Biomarkers in RA Management Identify healthy individuals who are susceptible to RA Diagnose RA early in its disease course Predict long-term disease severity Identify patients who require early and aggressive treatment Prevent overtreatment in patients who do not need aggressive therapy Predict the likelihood of response to specific treatments Predict the risk of side effects to specific treatments Monitor response to RA treatment Understand the reason for nonresponse or loss of response Determine next steps in patients with an inadequate response to current treatment Identify patients who may be able to have a drug-free remission ACPA/Anti-CCP Antibodies RA develops as a result of complex interactions between genetic and environmental risk factors. Smoking and other toxic stimuli can trigger a range of cellular responses associated with RA. 10 One major stress response is a process called citrullination. During citrullination, enzymes alter the chemical structure of proteins by metabolizing the amino acid arginine into citrulline. Many patients with RA are unable to tolerate citrullinated proteins and develop autoantibodies against these modified proteins. These autoantibodies, called ACPAs, are highly specific to RA. 10 Compared with RF, ACPA is more sensitive and more specific for RA, providing better utility as a diagnostic marker. 11 As a result, clinicians have recently shifted towards using ACPA instead of RF in the diagnosis of RA. 12 Laboratory testing for ACPA has undergone several changes since the first commercially available assay was released in The first assay used a synthetic cyclic citrullinated peptide (CCP) as a testing substrate, and antibodies that reacted to this test were called anti-ccp antibodies. This first-generation CCP (CCP1) assay detected autoantibodies in 53% of patients with established RA, with a specificity of 96%. 13 Over the past decade, several second-generation (CCP2) and third-generation (CCP3) assays that test for different subtypes of anti-ccp antibodies have been released. The newest tests detect an even wider range of autoantibodies, including those against non-cyclic citrullinated peptides. To reflect this change, the term ACPA has replaced anti-ccp antibody. 14 Testing for ACPA continues to evolve. In 2012, researchers described a new ACPA testing technique that uses a microarray to simultaneously analyze more than 100 autoantibodies associated with RA. 15 The goal of microarray testing is to identify new subgroups of RA patients based on unique autoantibody profiles who require different treatment approaches to best manage their RA. 4 Rheumatology Nurse Newsletter: Issue 4 of Volume 6

5 MY EXPERIENCES WITH BIOMARKERS IN CLINICAL CARE KORI DEWING, DNP Will I be crippled and in a wheelchair in 5 years? Will this medication work for me? Am I feeling better because of the medication or is it all in my head? Will I be able to continue to work and do my job? These are some of the most common questions I hear from my patients diagnosed with inflammatory arthritis. They desperately want me to magically reveal the future. I wish it were that easy. Unfortunately, no one dispensed a crystal ball upon nurse practitioner graduation. So while I do not (yet) have the ability to foresee the future, I explain to my patients that there are certain clues that can help predict their likely course of disease and guide our choice of therapeutic options. For instance, I tell seropositive patients that their rheumatoid factor and anti-ccp levels are associated with increased severity of disease, and warn them that they have a higher likelihood of developing erosive, crippling disease without appropriate intervention. During every clinical visit, I calculate my patients RAPID3 scores and talk to them about how they are feeling. Additionally, I use their acute phase reactant measurements to monitor for disease activity. My electronic medical record allows me to quickly develop and share a graph of their ESR, CRP, and RAPID3 scores over time. Because ESR and CRP measurements can be used to determine disease activity, I can also use these graphs (along with RAPID3 scores) to demonstrate patients improvement, or lack thereof, to a given treatment regimen. 1,2 Recently, I met with Nancy, a 38-year-old patient with RA diagnosed 3 years ago who was being treated with adalimumab and methotrexate. Nancy and I usually meet every 3 months for a regular monitoring visit, but she had come to see me outside of our normal schedule because she wasn t feeling well and had increased joint pain, swelling, and fatigue. Despite her pain, she was reluctant to consider a change in her medications. She instead asked for a quick fix to get her through what she thought was simply an acute flare of her RA. However, when I brought up her history and graphed out her ESR, CRP, and RAPID3 scores, she changed her mind and agreed to switch to a different biologic. Using these graphs demonstrated to her that, while she had a good initial response to her anti-tnf with normalization of acute phase reactants and meaningful improvement in her RAPID3 score, her last three measurements had gradually gotten worse and her RAPID3 score was even higher than at initial diagnosis. She could visually see that this was a trend, not just an isolated and short-lived flare. Although I use biomarkers in my daily practice to inform clinical decision making, I do not (yet) have a fancy machine that can scan a patient and predict the future. Every patient is different, and treatment needs to be tailored according to disease activity and co-morbidities. However, the hope is that someday, additional biomarkers will enable us to better predict who needs which drugs at what dose for how long to control their disease, prevent disability, and enable them to live a normal life. References 1. Nakamura RM. Progress in the use of biochemical and biological markers for evaluation of rheumatoid arthritis. J Clin Lab Anal. 2000;14(6): Smolen JS, Van der Heijde DM, St Clair, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006;54(2): ACPA-Positive RA Categorizing RA into ACPA-positive and ACPA-negative subgroups was a major leap forward in understanding the spectrum of RA. 16 ACPA-positive and ACPA-negative RA differ in several important aspects. The most prominent genetic risk factors for RA predispose patients to developing ACPA-positive RA, but they do not increase the risk of ACPA-negative disease (see page 6 for more information on genetic markers). 16 In addition, the presence of ACPA predicts greater disease activity and faster radiological progression, even with aggressive RA treatment. 11 Recent studies of ACPA-positive individuals provide new insights into the pathophysiology of RA that challenge longheld beliefs. ACPAs can be detected years before any clinical symptoms of RA emerge. One recent study examined bone loss in healthy individuals who tested positive for ACPA but had no signs or symptoms of arthritis. These patients underwent ACPA testing for unrelated medical purposes and were referred to a rheumatology clinic because of their positive test results rather than any joint complaints. Despite the lack of synovitis or elevated acute phase reactants, the ACPA-positive individuals had significant changes in bone architecture. Compared with healthy ACPA-negative controls, the ACPApositive individuals had significantly less total bone volume (P=0.001) and significantly lower bone mineral density (P=0.003) measured at the metacarpal heads. In addition, imaging studies of the metacarpal heads of the second and third digits showed significantly more abundant pre-erosion changes in the ACPA-positive individuals versus controls (P=0.0005). These cortical bone changes included very thin and porous bone. 17 These findings challenge the traditional understanding of joint damage in RA, which holds that bone damage is exclusively caused by long-term exposure to inflammation. Some evidence also suggests that ACPA can directly contribute to bone loss by stimulating monocytes to differentiate into bone-resorbing osteoclasts. 10 Inflammatory Markers Acute phase reactants, including ESR and CRP, are markers of inflammation. 4 These markers correlate with disease activity in patients with RA. However, ESR and CRP are also elevated in many other cases of systemic inflammation, and their role as diagnostic markers are limited by a lack of specificity for RA. 18 Tests for acute phase reactants are routinely available and are easy to perform, making ESR and CRP the most widely used biomarkers for evaluating inflammation in RA. 19 In addition, as part of the ACR s 20% improvement criteria (ACR20), acute phase reactants are the most commonly used markers of treatment response. 20 Despite their widespread use, however, tests for ESR and CRP have important limitations. Many patients with newly diagnosed RA have normal ESR To claim CE credits after reading this issue of Rheumatology Nurse, go to Rheumatology Nurse Newsletter: Issue 4 of Volume 6 5

6 MY EXPERIENCES WITH BIOMARKERS IN CLINICAL CARE JOYCE M. KORTAN, RN In talking recently to several of my professional colleagues, it became clear that the only biomarkers that the majority of rheumatology nurses understand with any depth are the CRP and ESR. These biomarkers are obviously useful in predicting treatment response, but many nurses may not understand the reasoning for testing both, much as I didn t when I entered the field more than 20 years ago. Over the years, I have talked with many providers regarding their reasoning for watching both measures of systemic inflammation and saw how there may be discordance with the results of these two tests. This discordance may be the clue to an individual patient s diagnosis. In my clinic, we recently saw a 47-year-old male with an elevated ESR and normal CRP who proved to be a very interesting case. The patient presented with arthralgias and myalgias, prompting the ordering of several lab tests to assist with our diagnosis. His polyarthritis actually resembled RA, with a high RF but negative anti-ccp. Among the lab tests we ordered was a serum protein electrophoresis (SPEP). The rheumatologist felt a SPEP would not only assist with the diagnosis but also rule out other possible diagnoses such as a malignancy (an SPEP is often used to identify patients with multiple myeloma and other serum protein disorders, as well as polyclonal gammopathy). 1 Results of the SPEP showed that this patient indeed had a polyclonal gammopathy caused by hepatitis C; consequently, his elevated ESR was not due to inflammation. After a more thorough workup, we found out that the patient s joint pain was a side effect of ribavirin, which he was taking to treat his hepatitis. In most situations, it is important to initially check both ESR and CRP as they can give clues to various conditions. In the short term, it may not be necessary to repeat ESR more frequently than every 1-2 weeks as it changes so slowly. As one rheumatologist explained to me, CRP rises and falls more quickly than ESR; consequently, ESR levels are better suited as a check for inflammation over the course of the last few weeks rather than the last few days. Understanding discordance of ESR and CRP and the reasons for their elevations may be useful when talking to patients about their diagnosis and lab tests. Elevations of these old and useful biomarkers may not always indicate inflammation, as we recently experienced, so being mindful of the limitations of these tests is also important. Reference: 1. O Connell TX, Horita TJ, Kasravi B. Understanding and interpreting serum protein electrophoresis. Am Fam Physician. 2005;71(1): and/or CRP levels (see Figure 1 on page 3). In a study of 1,744 patients with RA, 44% had normal CRP levels (<10 mg/l), 45% had normal ESR levels (<28 mm/hr), and 33% of patients had normal levels of both CRP and ESR. Furthermore, 15% of patients had normal ESR and CRP levels as well as negative RF test results. 6 Genetic Markers Approximately 60% of the risk of developing RA is attributable to genetic factors. 21 Much of the inherited risk of RA originates in the human leukocyte antigen (HLA)-DRB1 alleles encoding the shared epitope (SE). 22 Certain gene-environment interactions affect the magnitude of genetic risk factors. Smoking only modestly increases RA risk in patients who harbor no HLA-DRB1 SE alleles. However, in patients with 1 or 2 copies of the HLA-DRB1 SE allele, smoking increases the risk of RA by 6.5-fold and 21-fold, respectively. 23 In addition, the correlation between HLA-DRB1 and RA is stronger in ACPA-positive RA than in ACPA-negative RA. 24 Within the family of HLA-RB1 alleles, there are 136 possible HLA-DRB1 genotypes, and the relationship between individual genotypes and RA is complex. 25 One recent study described the interactions between specific HLA-DRB1 genotypes and ACPA-positive RA. Investigators evaluated 102 of the 136 possible HLA-DRB1 genotypes in 857 patients with ACPA-positive RA and 2,178 healthy controls. In total, 30 HLA-DRB1 genotypes were associated with an increased risk of ACPA-positive RA, 45 genotypes were neutral, and 27 genotypes demonstrated a protective effect against ACPA-positive RA. The results confirmed the SE hypothesis of RA susceptibility and suggest a dose effect that accounts for both copies of the HLA-DRB1 alleles in a genotype: All SE-positive genotypes with 2 affected alleles were high risk Most SE-positive genotypes with 1 affected allele were high risk (40%) or neutral (55%) Most SE-negative genotypes were neutral (45%) or low risk (47%) These findings help to clarify the role of HLA-DRB1 in RA susceptibility and have several potential applications in RA management. HLA-DRB1 genotyping may be useful in supporting the diagnosis of RA in a patient with undifferentiated arthritis, particularly before the emergence of an ACPA response. Genotyping may also be useful for genetic counseling in families affected by RA and in determining which family members to monitor closely for ACPA. 25 New Diagnostic Markers Approximately one-third of patients with early RA are considered seronegative, meaning that they will test negative for both RF and ACPA. 26 Negative autoantibody test results can delay the diagnosis and treatment of RA, leading to worse outcomes. 26 New biomarkers are needed to help identify seronegative patients early in the RA disease process eta The proteins are an abundant family of proteins involved in regulating signaling pathways that control diverse biological functions. The proteins are normally expressed within cells, but become externalized in response to certain disease triggers. One subtype of , eta, is found in the 6 To claim CE credits after reading this issue of Rheumatology Nurse, go to

7 synovial fluid of patients with inflamed joints. 27 The presence of extracellular eta provokes an auto-antibody response that is highly specific for RA and easily measured with an ELISA blood test. 28,29 The first potential application of a eta blood test is in the early diagnosis of RA. In a study of patients with joint pain, most patients (82%) who tested positive for eta at the start of the study developed RA within 4 years. By comparison, 62% of patients who tested negative for eta had not developed RA. 30 The eta test also improves the diagnostic sensitivity of standard biomarker testing. In a study of patients with early RA, 48% were positive for RF, 56% were positive for anti-ccp, and 67% were positive for eta. Combining all 3 tests identified 81% of RA patients. 31 The eta test may also have a role in identifying likely responders to anti-tnf therapy. In a group of 75 patients with established RA, 20% achieved clinical remission (DAS28-ESR <3.2) with TNF-targeted therapy. Lower baseline levels of eta predicted a better treatment response. The median baseline eta level for those who reached clinical remission was 0.7 ng/ml, compared with 2.5 ng/ml among those with a less robust response to anti-tnf treatment (P=0.015). 32 Importantly, the eta test predicted treatment response in patients with low CRP ( 10 mg/l). In the subgroup of patients with low CRP, the median baseline eta level was 0.0 ng/ml for patients who achieved clinical remission, compared with 3.5 ng/ml for patients who did not achieve remission with anti-tnf therapy (P=0.004). 32 Two options for testing eta became commercially available in Clinicians can order a eta test as a stand-alone blood test, or as part of a combined panel that measures RF, ACPA, and eta (IdentRA ). 33 Anti-CarP Antibodies First described in 2011, the anti-carbamylated protein (anti-carp) antibodies are another family of autoantibodies that appear to be active in RA. 34 The anti-carp antibodies are biologically distinct from ACPA, meaning that they can provide additional insight about the underlying disease process even in patients who are ACPA negative. In one study, different subtypes of anti-carp antibodies were detected in 16% (IgG) and 30% (IgA) of patients with ACPA-negative RA. 34 The presence of anti-carp antibodies in patients with ACPA-negative RA predicted a more severe disease course. 34 Testing for anti-carp antibodies may have a role in predicting the onset of RA. Another recent study examined the presence of anti-carp antibodies in patients with joint pain but no clinical signs of arthritis. A positive test for anti-carp significantly predicted the development of RA over the median follow-up time of 36 months. The anti-carp test correlated with RA even after controlling for RF and ACPA status. 35 A commercial assay for anti-carp antibodies is currently under development. 36 UH-RA.1, UH-RA.9, UH-RA.14, and UH-RA.21 Another promising marker for RA is the combination of four autoantibodies: UH-RA.1, UH-RA.9, UH-RA.14, and UH-RA.21. These newly identified autoantibodies are active in some patients with early RA, including patients who show no reactivity to RF or ACPA tests. 37 Detectable in the blood by a simple ELISA assay, these autoantibodies are now being tested together in a single biomarker panel. In a recent study, the biomarker panel was positive in 26% of the subgroup of patients with RA who tested negative for both RF and ACPA. 26 When added to standard RF and ACPA testing, the new biomarker panel identified about 7% more patients with newonset RA. With additional studies, these new biomarkers may find a role in closing the diagnostic gap in RA. MARKERS OF RA DISEASE ACTIVITY The Treat to Target (T2T) approach in RA involves the use of composite measures of disease activity to guide treatment decisions with the goal of achieving clinical remission or low disease activity. 38 Compared with care that alleviates the signs and symptoms of RA but carries no specific treatment goal, tight disease control with the T2T strategy reduces the accumulation of joint damage, protects against disability, and improves overall clinical outcomes. 39 To implement the T2T approach, rheumatology providers can select from a range of validated composite measures and choose the tool that works best for their practice. Commonly used measures include the disease activity score in 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID3) (Table 2). These scores rely heavily on subjective disease factors such as joint counts and pain, and results often vary between patients and observers. 18,40 Incorporating laboratory measures such as CRP and ESR brings additional objective information into disease activity scores, but these markers may not be relevant for all patients. As discussed earlier, a substantial proportion of patients with RA will have active disease despite normal CRP and ESR scores. 6 Table 2: Examples of Composite Measures of Disease Activity in RA PARAMETER Patient global assessment of disease activity Patient pain Patient physical function Clinician global assessment of disease activity COMPOSITE MEASURE DAS28 SDAI CDAI RAPID3 X X X X Tender joint count X X X Swollen joint count X X X Laboratory measure (ESR or CRP) CDAI = clinical disease activity index; CRP = C-reactive protein; DAS28 = disease activity score with 28 joint count; ESR = erythrocyte sedimentation rate; RAPID = routine assessment of patient index data; SDAI = simplified disease activity index. Source: Landewe R. Barriers to effective disease activity monitoring in rheumatoid arthritis clinical practice and implications for treat-to-target guidelines. Eur Musculoskeletal Review. 2011;6: X X X X X X Rheumatology Nurse Newsletter: Issue 4 of Volume 6 7

8 Figure 2. Roles of MBDA Biomarkers in Cellular Communication in RA IL-6 = interleukin-6; CRP = C-reactive protein; EGF = epidermal growth factor; MMP = matrix metalloproteinase; SAA = serum amyloid A; TNF-RI = tumor necrosis factor receptor type I; VCAM-1 = vascular cell adhesion molecule 1; VEGF = vascular endothelial growth factor. Source: Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8:e Multi-Biomarker Disease Activity Assay Assays that integrate information from multiple biomarkers into a single test provide clinicians with a comprehensive snapshot of a complex and heterogenous disease process. 41 The first multi-biomarker disease activity (MBDA) assay for measuring and monitoring disease activity in RA is now available. The MBDA assay was developed by screening approximately 400 candidate biomarkers to identify the strongest predictors of clinical disease activity in RA. 42 In total, 12 markers representing diverse biological pathways involved in RA were selected for inclusion into the MBDA assay (Figure 2). 41 These markers can be classified into the following functional categories: Acute-phase proteins: CRP and serum amyloid A (SAA) Cytokines and related proteins: interleukin-6 (IL-6) and TNF-receptor type I (TNF-RI) Adhesion molecules: vascular cell adhesion molecule-1 (VCAM-1) Matrix metalloproteinases (MMP): MMP-1 and MMP-2 Skeletal-related protein: YKL-40, or human cartilage glycoprotein 39 Growth factors: epidermal growth factor (EGF) and vascular endothelial growth factor A (VEGF-A) Hormones: leptin and resistin The MBDA assay compiles information about the 12 biomarkers into a single quantitative score. 41 This score ranges from 1 and 100, with defined thresholds for low (1-28), moderate (29-43), and high (>44) disease activity. 41 The MBDA score correlates well with other composite measures of disease activity, including DAS28-CRP, in seropositive and seronegative patients. 40 The MBDA score is also able to track changes in disease activity over time and discriminate between clinical responders and nonresponders. 40 As a new test, it is unclear how the MBDA assay will be incorporated into rheumatology practice. 43 Randomized clinical trials have shown that tight control of RA disease activity, with monthly clinical assessments and treatment adjustments, improves outcomes compared with less frequent monitoring Such an aggressive monitoring schedule, however, may be unfeasible in real-world practice. The MBDA score has been shown to accurately track RA disease activity over time. In a study of disease activity over one year in patients with RA, changes in the MBDA score correlated significantly with changes in standard composite scores of disease activity, including the DAS28-ESR, SDAI, and CDAI (P< for all comparisons). 43 More studies are needed to know which strategy for monitoring disease activity will give RA patients the best opportunity for disease control. The MBDA assay became a covered benefit for Medicare beneficiaries beginning in July For patients who are not covered under Medicare, the assay manufacturer offers several forms of help in gaining access to the test, including a reimbursement hotline, appeals support, and financial assistance for patients who need help with a copayment, coinsurance, or a deductible. 47 To claim CE credits after reading this issue of Rheumatology Nurse, go to

9 MARKERS ASSOCIATED WITH RA TREATMENT Current guidelines in RA present a conundrum for rheumatology providers. The guidelines emphasize the importance of achieving tight control of disease activity through frequent monitoring and treatment adjustment. However, there are no formal recommendations to guide the optimal sequence of biologic therapies. Approximately 30% to 50% of patients with RA will achieve clinical remission in response to the first anti-tnf therapy. 48 For patients with a less robust response, choice of what to do next switch to another anti-tnf agent or to another class of medications remains controversial. 49 Antidrug Antibodies Immunogenicity describes the potential for a drug to stimulate the immune system to develop antidrug antibodies (ADAs). The formation of ADAs was recently identified as a major mechanism driving the loss of response to biologic therapy over time. 50 ADAs bind to drug molecules, reducing the concentration of functional, unbound drug in the blood. As a result, ADAs have a dramatic effect on response to anti-tnf treatment. In a meta-analysis of patients with chronic inflammatory diseases, ADAs against adalimumab or infliximab reduced the likelihood of response by 68%. 51 Among patients with RA, ADAs against these agents reduced the likelihood of response by 97%. 52 Patients who develop ADAs are 3.5-times more likely to discontinue biologic therapy than patients without ADAs, in part due to poor tolerability. 52 The formation of ADA-drug complexes is associated with an increased risk of adverse events, including infusion and hypersensitivity reactions. 52 In a study of RA patients treated with adalimumab, patients with ADAs had nearly 8 times the risk of venous and arterial thromboembolic events compared to those without ADAs (HR, 7.6; P=0.025). 53 Monitoring patients for the production of antidrug antibodies may identify those with an increased risk of adverse events, as well as those whose response to anti- TNF therapy may diminish. 54 All monoclonal antibodies have the potential to trigger the production of ADAs, but most of our understanding of ADAs in RA involves studies of adalimumab and infliximab. 52 These agents have the highest immunogenicity of the anti-tnf therapies, with ADAs detected in up to 50% of patients treated with anti-tnf monotherapy. 50,52 The structure of etanercept is unique among the TNF inhibitors in that it does not trigger an immune response; patients rarely develop ADAs to etanercept. 51 Less is known about ADAs and the newer anti-tnf agents used in RA. 50,52 Individual studies have found ADAs in 13.5% of RA patients treated with single-agent golimumab and in 8.1% of patients treated with certolizumab pegol monotherapy. 7,55 The U.S. Food & Drug Administration (FDA) now requires testing new biological agents for immunogenicity before granting approval for clinical use. 56 Reducing the Risk of ADAs The immune system produces ADAs as part of an immune response against foreign proteins (i.e., anti-tnf agents). Using immunosuppressive therapy to dampen this response is a promising strategy. Concomitant immunosuppression with nonbiologic disease modifying antirheumatic drugs (DMARDs) has been shown to reduce the production of ADAs and prolong the survival of anti-tnf agents in the blood, resulting in better response to anti-tnf therapy. 50,51 Two recent meta-analyses measured the effects of nonbiologic DMARD therapy on ADA production in patients treated with anti-tnf therapy for a variety of chronic inflammatory diseases, including RA, psoriatic arthritis, Crohn s disease, and inflammatory bowel disease. Immunosuppressive therapy reduced the risk of developing ADAs by 41% to 68% averaged across all disease types. 51,52 In the subgroup of patients with RA, immunosuppressive therapy reduced the risk of developing ADAs by 85%. 52 For most patients, concomitant immunosuppression was in the form of MTX, although other nonbiologic DMARDs such as azathioprine were also used. 51,52 The use of oral corticosteroids during anti-tnf therapy had no effect on the development of ADAs. 52 In summary, the co-administration of nonbiologic DMARDs, particularly MTX, appears to protect against the formation of ADAs during anti-tnf therapy. These findings have important implications for RA treatment, particularly in light of recent trends in the use of biologic monotherapy. Up to 30% of patients with newly diagnosed RA are treated with a biologic agent alone, without a nonbiologic DMARD such as MTX. 57 Some RA experts now speculate that biologic monotherapy may not be an appropriate treatment choice in RA, as it leaves patients vulnerable to the risks associated with ADAs. 52 Concomitant immunosuppressive treatment with nonbiologic DMARD therapy may be needed to reduce these risks. 52 Testing for ADAs: Where Do We Stand? Testing for ADAs may allow clinicians to distinguish between different types of nonresponse and determine the best next steps for patients with a poor response to anti-tnf therapy. 58 One recent study included 292 RA patients who were being treated with etanercept. Some patients switched to etanercept after previous treatment with infliximab or adalimumab, while others started etanercept as their first anti-tnf agent. Among those who switched, the reason for non-response to the first anti-tnf agent influenced the magnitude of response to etanercept. Patients who switched because of a history of developing ADAs were just as likely to respond to etanercept as those who were anti-tnf naïve. The average reduction in DAS28 score in the two subgroups was 2.1 (prior infliximab) and 2.0 (prior adalimumab), respectively. By comparison, patients who switched anti-tnf agents for reasons other than ADAs were much less likely to respond to etanercept than those who switched anti-tnfs due to ADAs or were anti-tnf naïve. These patients had a mean reduction in DAS28 score of 1.2, which was significantly worse than in switchers with a history of ADAs (P=0.017) and anti-tnf naïve patients (P=0.001). 59 These findings support a role for ADA testing in patients with a poor response to infliximab or adalimumab. Among those with a poor response, patients who test positive for ADAs are likely to benefit from switching to etanercept. When the reason for poor response is not ADAs, clinical response to a second anti-tnf therapy is less likely. Although the reason for non-response in the absence of ADAs is unclear, one hypothesis suggests that TNF is not the main cytokine driving Rheumatology Nurse Newsletter: Issue 4 of Volume 6 9

10 Figure 3: Options for Detecting Anti-drug Antibodies TEST OPTIONS AND LIKELY RESULTS ADA Tests All anti-tnf antibodies and no ADAs DESCRIPTION OF SERUM SAMPLE Anti-TNF antibodies outnumber ADAs Equal amounts of anti-tnf antibodies and ADAs ABT=antigen-binding test; ADA=anti-drug antibodies; ELISA=enzyme-linked immunosorbent assay; PIA, ph-shift anti-idiotype antigen-binding test; TNF=tumor necrosis factor. Source: van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-tnf biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol. 2013;9: ADAs outnumber anti-tnf antibodies ELISA ABT - - +/- + PIA - +/- + + TNF Capture /- - disease activity in these patients. Therefore, patients without ADAs may be more likely to benefit from switching to a biologic therapy with a non-tnf mechanism of action (e.g., rituximab, abatacept, or tocilizumab). 59 The potential benefits of incorporating ADA testing into RA management include tighter control of disease activity and better clinical outcomes. Researchers recently proposed an algorithm for therapeutic drug monitoring for RA patients who are treated with biologic agents. The algorithm calls for testing serum drug levels every 3 months, and when drug levels are not detectable, testing for ADAs. The algorithm continues with additional branches (i.e., disease activity), and ultimately leads to recommendations to maintain current biologic therapy, switch to a drug with a different mechanism of action, or switch to a less immunogenic agent. Patients whose RA was managed according to the algorithm were nearly 8 times more likely to achieve a clinical response than those who were not (OR, 7.91; P<0.001), and nearly 10 times more likely to demonstrate low disease activity (OR, 9.77, P<0.001). 49 ADA Testing Options Testing for the presence of ADAs is technically challenging, and the test results are highly dependent on the type of assay used. 60 In general, ADA tests involve 1 of 4 testing methods (Figure 3). The enzyme-linked immunosorbent assay (ELISA) is the most commonly used antibody test due to its low cost and quick turnaround time. 50 With ELISA testing, a patient s blood sample is passed over a solid substrate coated in an anti-tnf drug. Any free ADAs present in the blood bind to the coating. These ADAs are detected using a radiolabeled form of the drug. 60 In the antigen-binding test (ABT), the patient s blood is processed to isolate the different types of antibodies present. Radiolabeled drug molecules are added to the sample, which will bind to any free ADAs. The amount of radiolabeled-drug/ ADA complexes is then measured. 60 The ELISA and ABT methods share a major limitation known as drug interference, in which the presence of a drug in the blood sample will disrupt the test results. These assays can detect only free ADA that is not already bound in ADA-drug complexes. This means that the production of ADAs must exceed the amount of drug in the patient s blood for a test to be positive. Because of drug interference, these tests likely underestimate the number of patients forming ADAs during anti-tnf therapy. 61 The third testing method was designed to overcome drug interference and allow the detection of ADAs in the presence of anti-tnf drugs. The ph-shift anti-idiotype antigen (PIA)- binding test is a modified form of the ABT that involves 3 steps. First, the ph of the patient s blood sample is lowered to dissociate the ADA-drug complex. Next, synthetic fragments of ADA (the Fab portion of rabbit ADA) are added to the sample to prevent the released drug molecules from re-binding to the patient s ADA. Lastly, the unbound ADA is measured using ABT. 60 This approach improves the detection of hidden ADAs in patients who are receiving anti-tnf therapy. In a study of 30 RA patients treated with adalimumab, the PIA test detected ADAs in 21 patients, while the ABT detected ADAs in only 5 patients. 61 The fourth testing option, called TNF capture, is a specialized test that measures the amount of functional, unbound anti-tnf drug in the serum. 60 Markers of Response to MTX Approximately 30% of patients with RA discontinue MTX treatment within 2 years of its initiation due to side effects or inadequate response. 62 Factors associated with poorer response to MTX include female gender, smoking, advanced disease stage, previous DMARD use, higher disease activity, and use without concomitant corticosteroids. 63 Patients with SE-positive HLA-DRB1 genotypes also have a poorer response to MTX treatment. 63 Drug Metabolites MTX is a prodrug, meaning that it must be metabolized to a biologically active form before it can exert its antiinflammatory activity in RA. MTX is enzymatically converted to MTX polyglutamates (MTXPGs). Some patients with RA harbor genetic mutations that disrupt MTX metabolism, leading to reduced conversion to the active form. 64 Measuring MTXPG metabolites allows clinicians to determine whether partial or nonresponders to MTX might benefit from increasing the MTX 10 To claim CE credits after reading this issue of Rheumatology Nurse, go to

11 MY EXPERIENCES WITH BIOMARKERS IN CLINICAL CARE JACQUELINE FRITZ, RN, MSN, CNS Mapping our patients progress can be a challenging and sometimes confusing process. Our goals have become somewhat clearer in recent years with the incorporation of treat-to-target standards, 1 but the process by which we measure our success, or lack thereof, can take numerous forms. Our practice uses two of the newer biomarker panels the Avise Polyglutamate (PG) test and the Vectra Disease Activity (DA) test to help us refine treatment and improve patient outcomes. Because ESR only measures inflammation and CRP only one inflammatory protein, we find these additional tools useful in managing more challenging patients to give us a clearer picture of what is going on with their disease. As we all know, while methotrexate (MTX) is one of the most effective and commonly prescribed DMARDs used in the treatment of RA, it comes with many potential side effects, including nausea, alopecia, fatigue, and bone marrow toxicity. The Avise PG blood test, which measures the active metabolites of MTX, gives us an objective determination of MTX absorption and helps us optimize dosage in patients who have been on MTX for at least three months. Results are reported as therapeutic (60 nmol/l), intermediate (20-60 nmol/l), or subtherapeutic (<20 nmol/l). 2 With this test, we can determine whether a patient is a partial or non-responder to MTX and may perhaps need a change in therapy. Another measurement tool we use in my practice is the VECTRA DA, a simple blood test that measures 12 biomarkers linked to RA. Results are reported as a single score between 1 and 100; correlates to high disease activity, moderate disease activity, and 1-29 low disease activity. The question of reimbursement is always an issue regarding these blood tests. The Vectra DA assessment is covered for all Medicare patients. The Avise PG is also covered by most insurance plans. In our office, we have had no problem with reimbursement with either test patients insurance is billed or charged to research statistical data. As an example of how we use these tests in specific patients, I ll introduce Fred, who came to our office with a history of right hand swelling in October We initially diagnosed him with highly active RA based upon his laboratory tests CCP>200, RF+, and numerous erosions. Fred was first placed on MTX 15 mg weekly and a prednisone taper, along with lansoprazole 15 mg. Prior to beginning therapy, his Vectra DA was 54 (high disease activity), his CRP 20 mg/l, and his ESR 33 mm/h. Three weeks after starting therapy, Fred said his pain was improved but that the MTX was making him nauseous. Consequently, we switched him to weekly MTX injections of 20 mg and added hydroxychloroquine 200 mg BID. Two months later, his right hand was swelling like a baseball mitt, although not causing significant pain. Repeat testing of his CRP and ESR showed values of 10 mg/l and 35 mm/h, respectively. Due to the lack of improvement, he was started on monthly abatacept 750 mg. Three months later, Fred was still suffering from swelling and pain in his right hand. His ESR and CRP had improved, but his Vectra score had only mildly decreased from 54 to 49, still at the high disease activity level. At this visit, we also drew an Avise PG, which demonstrated MTX levels below therapeutic despite weekly injections. Based on this information, Fred s dose of MTX was increased to 25 mg weekly. Four months later, Fred s Vectra score had decreased to 42, although there was still swelling in his right hand. After a brief bout with cellulitis, we again switched his biologic, this time to infliximab (400 mg every 6 weeks), while maintaining weekly injections of MTX 25 mg and hydroxychloroquine 200 mg BID. This combination finally did the trick, as the swelling in Fred s right hand subsided, his Vectra DA score decreased to 26, his ESR to 25, and his CRP to <4. Results from the Avise PG rose to the therapeutic range. When Fred was first diagnosed, because of his synovitis, he could not do anything for himself. Through the use of a variety of monitoring tools, we were able to make informed changes to guide his therapy and hopefully put his disease into a stable remission. References: 1. Smolen JS, Aletaha D, Bijlsma JW, et al; T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4): Dervieux T, Furst D, Lein DO, Capps R, Smith K, Caldwell J, Kremer J, et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis. 2005;64(8): dose or switching therapy. 65 The development of MTXPGs appears to play a role in the protective mechanism by which MTX reduces the risk of ADAs in patients treated with anti-tnf therapy. 66 Researchers evaluated the pharmacokinetics of MTXPG formation in a study of 61 patients who were treated with infliximab plus MTX for more than 3 months. ADAs were detected in 18% of patients. Despite similar infliximab dosing for all patients, those with ADAs had significantly lower median serum infliximab levels than those without ADAs (5.0 µg/ml vs. <0.5 µg/ml; P<0.001). MTXPG levels were also lower in patients with ADAs than in those without ADAs (22 nmol/l vs. 30 nmol/l; P=0.037) despite comparable MTX dosing. Overall, higher MTXPG levels were key to reducing the risk of ADAs and maximizing the systemic exposure to infliximab. MTXPG levels >25 nmol/l were associated with a 4.7-fold lower risk of ADAs (P=0.02). No patients with MTXPG levels >50 nmol/l tested positive for ADAs. 66 Other MTX Markers Researchers have evaluated other potential markers for MTX response. One promising marker is the concentration of folate measured in the red blood cells (RBCs). RBC folate is considered a better indicator of long-term folate status, whereas plasma/serum folate levels can fluctuate in response to diet. In an analysis of 285 patients with RA, lower pre-treatment levels of RBC folate predicted significantly higher DAS28 scores after 3 months of treatment with MTX (P=0.037). 67 Rheumatology Nurse Newsletter: Issue 4 of Volume 6 11

12 SUMMARY RA is a heterogenous disease with diverse clinical presentations and natural histories. Clinical assessments of disease activity that rely on patient-reported outcomes, such as joint counts and pain, capture the patient s subjective experience of RA. By comparison, biomarkers provide objective information about underlying biological pathways. Both types of information contribute to a complete understanding of a patient s health status. Rheumatology providers have been using biomarkers such as RF, ACPA, ESR, and CRP to classify RA for years. While these biomarkers provide important diagnostic and prognostic information for many patients with RA, many more questions about optimal RA care remain unanswered. New biomarkers promise to enhance diagnostic accuracy, assessment of disease severity, and prediction of treatment response. With the availability of new biomarker tests and biomarker panels, rheumatology providers may soon be able to select individualized treatment options that are most likely to result in good clinical outcomes for patients with RA. 12

13 REFERENCES 1. Tak PP. A personalized medicine approach to biologic treatment of rheumatoid arthritis: a preliminary treatment algorithm. Rheumatology (Oxford). 2012;51: Caveney EJ, Cohen OJ. Diabetes and biomarkers. J Diabetes Sci Technol. 2011;5: Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31: Aletaha D, Neogi T, Silman AJ, et al rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69: Singh JA, Furst DE, Bharat A, et al 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: Sokka T, Pincus T. Erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor are normal at presentation in 35%-45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol. 2009;36: Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-fourweek results of a phase III, multicenter, randomized, double-blind, placebocontrolled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60: Nielsen SF, Bojesen SE, Schnohr P, Nordestgaard BG. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ. 2012;345:e Willemze A, Toes RE, Huizinga TW, Trouw LA. New biomarkers in rheumatoid arthritis. Neth J Med. 2012;70: Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122: Emery P, Mcinnes IB, van Vollenhoven R, Kraan MC. Clinical identification and treatment of a rapidly progressing disease state in patients with rheumatoid arthritis. Rheumatology. 2008;47: Simard JF, Holmqvist M. Rheumatoid factor positivity in the general population. BMJ. 2012;345: e Schellekens GA, Visser H, de Jong BA, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000;43: Aggarwal R, Liao K, Nair R, Ringold S, Costenbader KH. Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum. 2009;61: Hansson M, Mathsson L, Schlederer T, et al. Validation of a multiplex chip-based assay for the detection of autoantibodies against citrullinated peptides. Arthritis Res Ther. 2012;14:R Trouw LA, Huizinga TW, Toes RE. Autoimmunity in rheumatoid arthritis: different antigens common principles. Ann Rheum Dis. 2013;72(suppl 2):ii132-ii Kleyer A, Finzel S, Rech J, et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis Mar 21. [Epub ahead of print] 18. Landewé R. Barriers to effective disease activity monitoring in rheumatoid arthritis clinical practice and implications for treat-to-target guidelines. Eur Musculoskeletal Review. 2011;6: Nam J, Villeneuve E, Emery P. The role of biomarkers in the management of patients with rheumatoid arthritis. Curr Rheumatol Rep. 2009;11: Felson D, Criteria ACORCTRI. A proposed revision to the ACR20: the hybrid measure of American College of Rheumatology response. Arthritis Rheum. 2007;57: MacGregor AJ, Snieder H, Rigby AS, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43: Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30: Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54: Mackie SL, Taylor JC, Martin SG, et al. A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population. Genes Immun. 2012;13: Balandraud N, Picard C, Reviron D, et al. HLA-DRB1 genotypes and the risk of developing anti citrullinated protein antibody (ACPA) positive rheumatoid arthritis. PLoS One. 2013;8:e De Winter L, Hansen W, Geusens P, et al. New autoantibodies as biomarkers for early and seronegative rheumatoid arthritis. EULAR 2013 Congress; Madrid, Spain; June 12-15, Abstract OP Kilani RT, Maksymowych WP, Aitken A, et al. Detection of high levels of 2 specific isoforms of proteins in synovial fluid from patients with joint inflammation. J Rheumatol. 2007;34: Maksymowych WP, Landewé R, van der Heijde D, Tak PP, Marotta A. Serum : a rheumatoid arthritis biomarker. Arthritis Rheum. 2011;63(suppl 10): Maksymowych WP, van der Heijde D, Landewé R, et al. Novel autoantibodies to eta are highly specific for rheumatoid arthritis. Arthritis Rheum. 2012;64(suppl 10): van Schaardenburg D, Dhaliwal R, Maksymowych W, Marotta A. Serum η precedes and independently predicts the development of RA. Arthritis Rheum. 2013;65(suppl 10): Marotta A, Bykerk V, Siminovitch K, et al. Extracellular η: an early RA pathogenic factor. Presented at: ACR/ ARHP 75th Annual Scientific Meeting; November 5-9, 2011; Chicago, IL. Abstract Maksymowych W, Bykerk V, Siminovitch K, et al eta sero-positivity marks more severe disease and titres inform response to therapy, also in patients with lower CRP. Presented at: EULAR 2013 Congress; June 12-15, 2013; Madrid, Spain. Abstract SAT PR Newswire. Quest Diagnostics launches novel rheumatoid arthritis tests. April 9, com/news-releases/quest-diagnosticslaunches-novel-rheumatoid-arthritistests html. Accessed December 2, Shi J, Knevel R, Suwannalai P, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A. 2011;108: Rheumatology Nurse Newsletter: Issue 4 of Volume 6 13

14 REFERENCES 35. Shi J, van de Stadt LA, Levarht EW, et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 2013;65: PR Newswire. Leiden University Medical Center licenses novel diagnostic for rheumatoid arthritis to INOVA Diagnostics. January 29, Accessed December 2, Somers K, Geusens P, Elewaut D, et al. Novel autoantibody markers for early and seronegative rheumatoid arthritis. J Autoimmun. 2011;36: Smolen JS, Aletaha D, Bijlsma JWJ, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69: Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. 2010;69: Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken). 2012;64: Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8:e Ramanujan S, Centola M, Cavet G, McInnes IB. Multi-protein biomarker panel integrates critical pathophysiologic mechanisms in measurement of RA disease activity. Presented at: The European League Against Rheumatism Annual Congress; June 16-19, 2010; Rome, Italy. Abstract FRI Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford). 2013;52: Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364: Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66: Schipper LG, van Hulst LT, Grol R, van Riel PL, Hulscher ME, Fransen J. Meta-analysis of tight control strategies in rheumatoid arthritis: protocolized treatment has additional value with respect to the clinical outcome. Rheumatology (Oxford). 2010;49: Crescendo Bioscience. Crescendo access and reimbursement essentials. Vectra DA Web site. insurance.php. Accessed December 2, Sesin CA, Bingham CO 3rd. Remission in rheumatoid arthritis: wishful thinking or clinical reality? Semin Arthritis Rheum. 2005;35: Garcês S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis May 11. [Epub ahead of print] 50. Jani M, Barton A, Warren RB, Griffiths CE, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) Aug 14. [Epub ahead of print] 51. Garces S, Demengeot J, Benito-Garcia E. 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: Maneiro JR, Salgado E, Gomez-Reino JJ. Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta-analysis. JAMA Intern Med. 2013;173: Korswagen LA, Bartelds GM, Krieckaert CL, et al. Venous and arterial thromboembolic events in adalimumabtreated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 2011;63: Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21: Fleischmann R, Vencovsky J, van Vollenhoven RF, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous diseasemodifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68: US Food and Drug Administration. Guidance for industry. Immunogenicity assessment for therapeutic protein products. Rockville, MD: US Department of Health and Human Services; Yazici Y, Shi N, John A. Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy. Bull NYU Hosp Jt Dis. 2008;66: Higgs R. Rheumatoid arthritis: Immunogenicity is predictive of future treatment success in RA. Nat Rev Rheumatol. 2011;7: Jamnitski A, Bartelds GM, Nurmohamed MT, et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011;70: van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-tnf biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol. 2013;9: van Schouwenburg PA, Bartelds GM, Hart MH, Aarden L, Wolbink GJ, Wouters D. A novel method for the detection of antibodies to adalimumab in the presence of drug reveals hidden immunogenicity in rheumatoid arthritis patients. J Immunol Methods. 2010;362: Hider SL, Silman AJ, Thomson W, et al. Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann Rheum Dis. 2009;68: Romão VC, Canhão H, Fonseca JE. Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? BMC Med. 2013;11: Dervieux T, Furst D, Lein DO, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 2004;50: Avise PG test for rheumatoid arthritis. San Diego, CA: Cypress Bioscience, Inc. 66. Dervieux T, Weinblatt ME, Kivitz A, Kremer JM. Methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arthritis. Ann Rheum Dis. 2013;72: de Rotte MC, de Jong PH, Pluijm SM, et al. Low baseline folate in erythrocytes is associated with non-response in rheumatoid arthritis patients on methotrexate. Arthritis Rheum. 2013;65:

15 COMPLEMENTARY AND ALTERNATIVE MEDICINE IN RHEUMATOLOGY: THE NURSING PERSPECTIVE VICKY RUFFING, RN According to the National Center for Complementary and Alternative Medicine (NCCAM), nearly 40% of Americans incorporate practices outside of mainstream or conventional medicine to help manage specific conditions, their overall wellbeing, or both. 1 While complementary and alternative medicine are often lumped together, it is important to recognize their differentiating characteristics complementary medicine involves the use of non-traditional therapies in addition to traditional medications, while alternative medicine refers to the use of non-traditional medications in place of traditional medications. While use of alternative medicine is relatively uncommon in today s society, I see many patients with rheumatic disease incorporating complementary medicine into their overall care. As scientific evidence backing the use of complementary medicine across the healthcare spectrum comes to light, the integration of personal healthcare is becoming more accepted in our community. Mind and body practices have become easily accessible for many of us. Examples include yoga, tai chi, acupuncture, mediation, guided imagery, and massage. I find myself specifically recommending yoga and tai chi more and more often as I have seen my patients benefit from their use. Scientific studies are proving their benefits as well. 2,3 The interest in natural products has also increased. Natural products include herbs, botanicals, vitamins, probiotics, and minerals. Some of these products have been studied in large controlled trials, demonstrating both positive and negative results. However, the use of most natural products remains unstudied, leaving much to be learned about the safety and potential interactions with other medications. Here is a brief review of the efficacy and safety of some of the more common natural products I come across on a day-to-day basis. It should be noted that the trials detailed were primarily exploratory in nature and results would need to be validated in larger, clinical trials before any substantive conclusions are reached. TURMERIC Turmeric has been used for centuries in Indian medicine to treat inflammatory disorders and is commonly incorporated into dietary supplements in the Western world to treat and prevent arthritis. A 2006 clinical trial by Funk et al at the University of Arizona tested its efficacy by treating rats with RA with different preparations and dosages of turmeric extracts to determine its ability to prevent and treat disease. In the study, some rats received treatment before developing RA-like symptoms, others afterward. 4 The results, primarily measured in terms of joint swelling, suggested that an extract processed to contain only curcuminoids the major component of turmeric may be more effective for preventing RA symptoms than a more complex extract containing curcuminoids in addition to other compounds. The authors also noted that the curcuminoid-only formulas appeared safer and more effective at lower doses. Also, the researchers found that the compounds had greater effectiveness when the rats were treated before, instead of after, the onset of inflammation. 4 THUNDER GOD VINE Thunder god vine is a perennial vine found in Japan, Korea, and China that has been used for at least 400 years to treat RA, lupus, and multiple sclerosis. Results from a small 2002 study funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, which looked at the impact of multiple doses of an extract of thunder god vine among patients with RA who had failed previous DMARD therapy, showed some therapeutic benefit among individuals treated with either high-dose (360 mg/day) or low-dose (180 mg/day) extracts. 5 While these results are potentially encouraging, it must be noted that thunder god vine can cause severe side effects and can be poisonous if not carefully extracted from the skinned root. Other parts of the plant including the leaves, flowers, and skin of the root are highly poisonous. Thunder god vine can also cause hair loss, headache, menstrual changes, and skin rash. Thunder god vine has been found to decrease bone mineral density in women who take the herb for 5 years or longer. This side effect may be of particular concern to women who have osteoporosis or are at risk for the condition. Thunder god vine also contains chemicals that might decrease male fertility by changing sperm. GREEN TEA In 2008, NCCAM-funded investigators at the University of Maryland and Rutgers University examined the effects of green tea polyphenols on RA by using a rat model. The animals consumed green tea in their drinking water (controls drank water only) for 1 to 3 weeks before being injected with heat-killed Mycobacterium tuberculosis H37Ra to induce arthritis. 6 In their commentary, the researchers suggest that green tea may affect arthritis by suppressing both cytokine IL-17 (an inflammatory substance) and antibodies to Bhsp65 (a disease-related antigen), and inducing cytokine IL-10 (an antiinflammatory substance). Therefore, they recommend that green tea be further explored as a dietary therapy for use together with conventional treatment for managing RA. 6 OMEGA-3 FATTY ACIDS A 2012 systematic review concluded that the types of omega-3s found in seafood and fish oil are modestly helpful in relieving symptoms of RA. In the studies included within the review, many participants reported a modest reduction in morning stiffness, less joint swelling and pain, and less need for anti-inflammatory drugs to control their symptoms when taking omega-3s. 7 Because many of our RA patients use complementary medicines as part of their treatment regimen, it is important that the nursing community is able to educate patients about their efficacy and side effects. While robust clinical trials in this area are rare, data is emerging that could help better guide our patients interested in nontraditional approaches to care in the near future. References: 1. Barnes PM, Bloom B, Nahin R. CDC National Health Statistics Report #12. Complementary and Alternative Medicine Use Among Adults and Children: United States, Uhlig T. Tai Chi and yoga as complementary therapies in rheumatologic conditions. Best Pract Res Clin Rheumatol. 2012;26(3): Ward L, Stebbings S, Cherkin D, Baxter GD. Yoga for Functional Ability, Pain and Psychosocial Outcomes in Musculoskeletal Conditions: A Systematic Review and Meta-Analysis. Musculoskeletal Care Jan Funk JL, Oyarzo JN, Frye JB, et al. Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis. J Nat Prod. 2006;69(3): Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. 2002;46(7): Kim HR, Rajaiah R, Wu QL, et al. Green tea protects rats against autoimmune arthritis by modulating disease-related immune events. J Nutr. 2008;138: Miles EA, Calder PC. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. British Journal of Nutrition. 2012;107(Suppl 2):S171 S184. Rheumatology Nurse Newsletter: Issue 4 of Volume 6 15

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