Rheumatoid Arthritis - Evidence to Optimize Outcomes in Patients

Transcription

1 Applying the Evidence to Optimize Outcomes in Patients With Rheumatoid Arthritis Presented by The University of Kentucky College of Medicine and developed through a strategic educational facilitation with Gullapalli and Associates, LLC. Date of Release: March 6, 2009 Date of Expiration: March 6, 2010 Estimated Time To Complete This Educational Activity This activity should take approximately 2.0 hours to complete. Supported by a multi-sponsored educational grant from Genentech, Biogen Idec., and Bristol-Myers Squibb, Inc. Statement of Need The RAVFP e-monograph is intended to be a comprehensive set of analytical, diagnostic, and planning resources that will assist participants in reinforcing the overall goals, objectives, and learnings derived from the RAVFP educational platform. The goal of the e-monograph is not to render any statements or conclusions surrounding clinical data, guidelines, or models, but rather to enlighten, reinforce, and provide access to information and best practices attained from the RAVFP activity through the following: Understand the long-term implications of biologic therapy on joint stability and mobility Identify the appropriate administration and dosage of approved biologics in patients with RA Select appropriate effective and safe therapies for RA patients with comorbid conditions Understand the benefits of a multidisciplinary approach to the treatment of rheumatic disorders in enhancing patient care and outcomes Target Audience The intended audience for this educational activity includes rheumatologists, rheumatology nurses, and nurse practitioners. There are no prerequisites to participate in this educational activity. Learning Objectives At the conclusion of this activity, participants should be better prepared to: Understand the long-term implications of biologic therapy on joint stability and mobility Identify the appropriate administration and dosage of approved biologics in patients with RA Select appropriate effective and safe therapies for RA patients with comorbid conditions Understand the benefits of a multidisciplinary approach to the treatment of rheumatic disorders in enhancing patient care and outcomes Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the University of Kentucky College of Medicine and Gullapalli and Associates, LLC. The University of 1

2 Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky College of Medicine designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. The University of Kentucky College of Medicine presents this activity for educational purposes only. Participants are expected to utilize their own expertise and judgment while engaged in the practice of medicine. The content of the presentations is provided solely by presenters who have been selected for presentations because of recognized expertise in their field. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky College of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. Method of Participation Participants should complete the online activity, posttest and evaluation in their entirety in order for a statement of credit to be issued. Instructions: Following completion of the activity: 1. Visit and enter the activity code MEN Log in or register for a free account 3. Complete the posttest and evaluation (a passing score of 70% is required for posttest). 4. Get Credit. A printable credit will be available. Credit is available through March 6, COURSE DIRECTORS AND CURRICULUM REVIEWERS Allan Gibofsky, MD, JD, FACP, FCLM Professor of Medicine and Public Health Weill Medical College of Cornell University Attending Rheumatologist Hospital for Special Surgery New York, NY Katherine Temprano, MD Assistant Professor of Internal Medicine Division of Rheumatology University of Kentucky College of Medicine Lexington, KY Faculty Disclosure As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of The University of Kentucky College of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The presenting faculty or author reported the following: Allan Gibofsky, MD, JD, FACP, FCLM, discloses the following: 2

3 Speakers Bureau for Abbott, Amgen, Bristol-Myers Squibb, Pfizer, and Wyeth Consultant for Roche Owns stock in Abbott, Amgen, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer Katherine Temprano, MD, discloses the following: Speakers Bureau for Takeda Off-Label Product Discussion No faculty members or authors have indicated that this activity will include off-label information. Disclaimer The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The University of Kentucky College of Medicine name or the Gullapalli and Associates, LLC name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients. Copyright Information Copyright 2009 The University of Kentucky College of Medicine. All rights reserved. No part of this syllabus may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations embodied in articles or reviews. The Rheumatoid Arthritis Visiting Faculty Program 3

4 emonograph Applying the Evidence to Optimize Outcomes in Patients With Rheumatoid Arthritis Introduction RA is a systemic autoimmune disease that leads to chronic inflammation and progressive destruction of the synovial joints. 1 Bone erosion is the major cause of disability among patients with RA. 2 Because of systemic inflammation, patients with RA are also at increased risk for developing coronary artery disease, infection, and lymphoma. 2 Results of studies using sensitive imaging techniques, such as magnetic resonance imaging and ultrasonography, have demonstrated that inflammation and joint damage in RA occurs rapidly, within weeks of symptom onset. 3 In addition, data from recent randomized, controlled trials (RCTs) have shown that early treatment with disease-modifying antirheumatic drugs (DMARDs), including tumor necrosis factor (TNF)-α antagonists and DMARD combinations, prevents joint destruction and improves patient outcomes Based on these findings, the treatment paradigm for RA has shifted toward early and aggressive therapy targeting the inflammatory response with DMARDs, in order to prevent joint damage and loss of functional capacity, both of which are directly related to increased morbidity and mortality. 1,3 This more aggressive treatment approach is reflected in current evidence-based clinical practice guidelines American College of Rheumatology (ACR) guidelines recommend that in addition to effective pharmacologic therapy, a multidisciplinary approach to care, with a focus on patient education, is important for ensuring optimal patient outcomes. 11 After an individualized treatment regimen has been initiated, frequent patient monitoring and assessment of therapeutic strategies until goals are achieved is critical. 10 Developing individualized goals, such as controlling joint pain and discomfort, maintaining and improving physical functioning, enhancing quality of life (QOL), and preventing complications, is an integral part of an overall care plan. 13 The ultimate treatment goal, however, is to achieve disease remission. 3,13 Although this may seem challenging in clinical practice, it is attainable in many patients 65% of patients in the Tight Control for Rheumatoid Arthritis (TICORA) study achieved this goal with intensive monitoring and adjustment of therapy based on disease activity. 7 In addition to improvements in patient care that may be achieved by applying these evidencebased guidelines in clinical practice, health care professionals have other resources at their disposal to help achieve optimal patient outcomes. For example, the ACR has developed quality performance indicators for patients with RA that can be easily incorporated into clinical practice. 14 The ACR also provides a practice improvement module that walks health care professionals through the process of evaluating and redesigning current practice systems based on quality improvement methods. Because outcomes for patients with RA can be optimized with effective treatment and monitoring, it is imperative that health care professionals take appropriate action to improve the process of care for such patients. 15 As experts in the field of RA treatment and management, rheumatologists must assume a leadership role in implementing clinical quality improvement strategies. The Impact of RA 4

5 RA is the most common autoimmune disease, affecting 1% to 1.5% of the population worldwide 16 and about 1.3 million Americans. 17 The disease disproportionately strikes women, who comprise approximately 75% of those affected. In fact, 1% to 3% of women will develop RA in their lifetime. 17 Although the reason for this is unknown, it has been attributed to hormonal effects on immune function. 16 A genetic predisposition for RA also exists, with the prevalence of the disease varying across racial and ethnic groups. For example, RA is more common among North American Pima Indians and southeast Alaskan Indians than among the general population. 16 The incidence of RA increases dramatically during adulthood, peaking between 40 and 60 years of age. 16 RA exerts a devastating impact, in part because it strikes during the most productive time of a person s life. 16 In addition to targeting the joints, the inflammation associated with RA can also cause multiple extra-articular manifestations. 16 The effects of RA, which can range from discomfort to death, include the following: Joint pain, stiffness, and discomfort 13 Joint deformities 13 Decreased functional capacity 13 Increased probability of no longer working 18,19 Decreased QOL on a physical, social, and emotional level 13,20 Increased health care costs 2 Increased mortality (life expectancy shortened by 5 to 7 years) 13 Early and effective treatment of RA, achieved by targeting the inflammatory response, can alleviate symptoms and prevent long-term complications. 10 The Evidence for Early, Aggressive Treatment in Patients With RA The window of opportunity for early treatment of RA is supported by data from imaging studies, as well as from RCTs evaluating early therapeutic strategies. 3 Based on imaging studies, about 90% of patients exhibit radiologic damage at 2 years. 3,21 Clinical trials have demonstrated that early DMARD therapy is associated with improved patient outcomes; conversely, delayed treatment appears to be detrimental. 3 In fact, disease duration is one of the most important factors predicting treatment response in patients with RA. 22 The Window of Opportunity Data from small studies, meta-analyses, and large RCTs of DMARDS consistently support the fact that treatment during the window of opportunity is associated with improved patient outcomes. In a small study of 63 patients with mild, untreated, early inflammatory arthritis who received a single dose of corticosteroids, more individuals who were treated within 12 weeks achieved clinical disease remission, defined as the absence of symptoms or signs in a patient receiving no antiinflammatory treatment. 23 At 6 months following a corticosteroid injection, 49 of the 63 patients (78%) had persistent inflammatory joint disease and 14 (22%) achieved clinical disease remission. Regression analysis showed that disease duration was the only factor significantly associated with persistent arthritis (P<.05). The strongest predictor of persistent disease was RA duration of >12 weeks. 23 5

6 A recent meta-analysis of 12 studies (6 open-label extensions of RCTs and 6 observational cohort studies) evaluated the association between delay to treatment initiation and progressive radiographic joint damage in patients with early RA (disease duration <2 years at presentation). 24 The average time between early and delayed treatment was 9 months. 24 A significant reduction in radiographic progression was observed in patients treated early based on annualized rates of progression (standardized mean difference, 0.19; 95% confidence interval [CI], 0.34, 0.04), which corresponded to a 33% reduction (95% CI, 50, 16) in long-term progression rates compared with patients treated later on. 24 Anderson and colleagues 22 conducted an analysis of data from 14 RCTs (N=1435) in patients with RA to identify factors affecting response to treatment. Active treatments included methotrexate (MTX), the combination of cyclosporine plus MTX, the COBRA (COmbinatietherapie Bij Reumatoïde Arthritis) trial regimen of MTX plus sulfasalazine (SSZ) plus step-down prednisolone, 25 and a placebo-controlled trial of a new device (Prosorba column; Cypress Bioscience, Inc.; San Diego, CA). 22 Results of this analysis provide additional evidence that patients with RA of longer duration do not respond as well to treatment as do those who are treated early in the disease course. 22 The response rate was 53% for patients with 1 year of disease on any active treatment, compared with 43% in those with 1 to 2 years disease duration, 44% with 2 to 5 years disease duration, 38% with 5 to 10 years disease duration, and 35% for those with >10 years disease duration (P=.001). 22 There was a decreased response for each of 7 ACR core set variables in patients with a longer duration of RA (see Figure 1). 22 Figure 1. ACR Response by RA Disease Duration 22 The proportion of patients in 14 trials improving by 20% in each of 7 ACR core set items within each disease duration category. ACR core set items included tender joint count (TJC), swollen joint count (SJC), erythrocyte sedimentation rate (ESR), patient assessment of disease severity (PTSEV), physician 6

7 assessment of disease severity (PHYSEV), grip strength (in 11 trials) or Health Assessment Questionnaire score (in 3 trials; GRIP/HAQ), and patient assessment of pain (PAIN). 22 Efficacy of TNF-α Antagonists in Early RA: Results of Pivotal Trials Results of pivotal RCTs demonstrate that combination therapy with a TNF-α antagonist plus MTX in individuals with early RA is superior to treatment with MTX alone in achieving improvement in patient outcomes, including signs and symptoms of RA, radiographic progression, and disease remission. 4-6 The Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE), a multicenter, randomized, double-blind, pivotal trial, evaluated the safety and efficacy of infliximab in 1004 MTX-naïve patients with early ( 3 years duration), active RA. Patients were treated with MTX (optimized to 20 mg/week by week 8) plus placebo, infliximab 3 mg/kg, or infliximab 6 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter. 5 The median disease duration was 0.6 years. The results reported at 54 weeks were as follows 5 : The median percentage of ACR improvement was higher in the MTX plus infliximab 3 mg/kg and MTX plus infliximab 6 mg/kg groups vs. the MTX plus placebo group (38.9% and 46.7%, respectively, vs. 26.4%; P<.001 for both comparisons) Radiographic progression was less in the MTX plus infliximab 3 mg/kg and MTX plus infliximab 6 mg/kg groups vs. the MTX plus placebo group (mean ± standard deviation changes in van der Heijde modification of the total Sharp score: 0.4 ± 5.8 and 0.5 ± 5.6%, respectively, vs. 3.7 ± 9.6; P<.001 for each comparison) The percentage of patients achieving disease remission at week 54, based on a Disease Activity Score in 28 joints (DAS28) of <2.6, is shown in Figure 2 (P=.065 for MTX plus infliximab 3 mg/kg vs. MTX plus placebo; P<.001 for MTX plus infliximab 6 mg/kg vs. MTX plus placebo) Of note, a higher incidence of serious infections, particularly pneumonia, was reported among infliximab-treated patients. 5 Figure 2. Remission Rates, Based on DAS28, in the ASPIRE Trial 5 The PREMIER study was a 2-year, multicenter, double-blind trial comparing the efficacy and safety of adalimumab plus MTX vs. MTX alone or adalimumab alone in 799 MTX-naïve patients with early (<3 years disease duration), aggressive RA. 4 Patients were treated with adalimumab 40 mg every 7

8 other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. More than half (57%) of patients had had RA for <6 months. Results of the study were as follows 4 : ACR 50% improvement (ACR50) was achieved in 62% of those on combination therapy, vs. 46% and 41% of patients receiving MTX monotherapy and adalimumab monotherapy, respectively; P<.001 for both); similar results were reported with ACR20, ACR70, and ACR90 response rates at year 1 and year 2 Radiographic progression (P.002) was significantly less in patients on combination treatment at year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) vs. patients in the MTX treatment arm (5.7 and 10.4 Sharp units, respectively) and the adalimumab treatment arm (3.0 and 5.5 Sharp units, respectively), at year 1 and year 2 As shown in Figure 3, 49% of patients in the combination therapy group achieved remission (DAS28 <2.6) at 2 years, vs. 25% of patients in both monotherapy groups (P<.001 vs. both adalimumab alone and MTX alone) 8

9 Figure 3. Clinical Remission (DAS28 <2.6) at Year 1 and Year 2 in the PREMIER Study 4 *P<.001 vs. adalimumab alone and vs. MTX alone. 4 The incidence of adverse events was similar in all 3 treatment groups. 4 The Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET) trial compared outcomes in 542 MTX-naïve patients with early (3 to 24 months duration) moderate to severe RA. 6 Patients were treated with MTX alone (titrated up to 20 mg/week by week 8) or with the same regimen of MTX plus etanercept 50 mg/week. Results at 52 weeks were as follows 6 : Clinical remission (DAS28 <2.6) was achieved by 50% of patients in the combination therapy group (132/265), compared with 28% (73/263) in the MTX monotherapy group (effect difference, 22.05%; 95% CI, 13.96% to 30.15%; P<.0001; see Figure 4). Of note, there was a significant difference in the proportion of patients in DAS28 remission at week 2, which persisted throughout the study period Radiographic nonprogression was achieved by 80% (196/246) of patients receiving combination therapy and 59% (135/230) of patients receiving MTX monotherapy (effect difference, 20.98%; 95% CI, 12.97% to 29.09%; P<.0001) 9

10 Figure 4. COMET DAS28 Remission (<2.6) Over 52 Weeks of Treatment 6 *P=.002; P< The rates of serious adverse events were similar between the 2 treatment groups. 6 The Early Rheumatoid Arthritis (ERA) study was the pivotal trial of etanercept in RA. It was conducted to evaluate the efficacy and safety of twice-weekly etanercept (10 or 25 mg) or weekly oral MTX (mean dose 19 mg per week) in 632 patients with active early RA (disease duration 3 years or less). 26 Patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having ACR20, ACR50 and ACR70 improvement in disease activity during the first six months (P<0.05). 26. Seventy-two percent of patients in the etanercept 25 mg group had no increase in the Sharp scale erosion score compared with 60% of patients in the methotrexate group (P=0.007). The majority of patients had no new or worsening erosions during the study. 26 Of note, etanercept also had a more immediate effect to inhibit radiographic progression. Significantly more patients in the methotrexate group had adverse events than patients in both etanercept groups (p=0.04 vs. etanercept10 mg, P=0.02 vs. etanercept 25 mg). 26 Radiographic images of 2 proximal interphalangeal (PIP) joints of a 50-year-old male participant in the long-term extension of the Early Rheumatoid Arthritis (ERA) trial, compared at baseline and after 4 years, provide visual impact of the long-term benefits of early treatment with TNF-α antagonists (see Figure 5). 27 These radiographs demonstrate clear evidence of recortication. At baseline, this DMARD-naïve patient had disease duration of 2 months, a positive serum rheumatoid factor, 39 tender joints, 29 swollen joints, serum C-reactive protein (CRP) level of 4.5 mg/dl, erythrocyte sedimentation rate (ESR) of 77 mm/h, baseline Health Assessment Questionnaire (HAQ) score of 0.88, and DAS28 CRP of After only 1 month of treatment with etanercept 10 mg, dramatic clinical improvement was reported in this patient, with an ACR70 10

11 response and no tender or swollen joints. 27 The clinical improvements were maintained for 4 years of treatment

12 Figure 5. Radiographs of 2 PIP Joints: Baseline and After 4 Years of Etanercept Treatment 27 Left panels show radiographs of the 3rd left PIP joint. At baseline, the radial and ulnar surfaces show irregularity and scalloping, with disruption of the cortex. At 4 years, the irregularities are markedly improved and recortication is evident. Right panels show radiographs of the 2nd right PIP joint. At baseline, the radial surface of the joint shows irregularity and cortical disruption. At 4 years, recortication is evident. 27 Overall, these results indicate that in patients with early, active RA, combination therapy with MTX plus a TNF-α antagonist provides greater clinical, radiographic, and functional benefits than treatment with MTX alone or with adalimumab alone. 5,6 Based on the totality of the data, evidence of radiographic damage before intervention no longer can be reasonably justified. 3 The Importance of Tight Control Two recent clinical trials confirm that improved outcomes are achieved with early, aggressive therapy incorporating close follow-up and treatment escalation in patients who have not achieved targets for RA control. 7,8 The single-blind TICORA study included 111 patients with RA for <5 years who were randomized to a strategy of routine outpatient care or intensive outpatient management focused on sustained, tight control of disease activity with an oral regimen of traditional DMARDs. 7 Patients in the usual-care group were seen every 3 months in a rheumatology follow-up clinic; no formal composite measure of disease activity was used in clinical decision-making. Patients in the tight-control group were evaluated based on a DAS of 3.6, 2.4, and 1.6, which represented high, moderate, and low disease activity, respectively, with treatment adjusted accordingly. 7 Patients with a DAS >2.4 at each 3-month assessment had an escalation in oral treatment based on the dosing protocol, unless they experienced toxic drug effects or declined therapy. Patients could also be treated with intra-articular corticosteroid injections. 7 Patients undergoing intensive treatment were more likely to be in remission compared with those receiving routine care (DAS <1.6: 36/55 [65%] vs. 9/55 [16%], respectively; odds ratio, 9.7; 95% CI, 3.9 to 23.9; P<.0001). 7 Intensive treatment resulted in statistically significant 12

13 improvements in median total Sharp score (interquartile range) compared with regular care: 4.5 (1 to 9.875) vs. 8.5 (2 to 15.5), respectively; P= The intensive treatment was well tolerated. It is interesting to note that drug-related toxic effects were actually more common in the routinetreatment group (85 adverse events reported in 42 of 55 patients) compared with the intensivetreatment group (46 adverse events reported in 32 of 55 patients). In the routine-care group, 38 of 89 (43%) new DMARD courses begun during the trial were discontinued because of drug-related toxic effects, compared with 20 of 129 (16%) in the intensive-care group. 7 The BeSt (Dutch acronym for Behandel Strategieë, or treatment strategies ) study was a multicenter, randomized, single-blind trial conducted to determine which of 4 aggressive treatment strategies resulted in the best outcome in 508 DMARD-naïve patients with early RA. 8 The following treatment regimens were compared 8 : Group 1 (n=126): sequential monotherapy started with MTX, then SSZ, then leflunomide, then MTX plus infliximab Group 2 (n=121): step-up combination therapy started with MTX, then MTX plus SSZ, then MTX plus SSZ plus hydroxychloroquine (HCQ), then MTX plus SSZ plus HCQ plus prednisone, then MTX plus infliximab Group 3 (n=133): initial combination therapy with tapered high-dose prednisone, started with MTX plus SSZ plus prednisone (tapered from 60 to 7.5 mg/day), then MTX plus cyclosporin A plus prednisone 7.5 mg/day, then MTX plus infliximab Group 4 (n=128): initial combination therapy with infliximab, started with MTX plus infliximab, then SSZ, then leflunomide The goal of this study was to reduce disease activity rapidly and persistently by tight monitoring and immediate adjustment of therapy in the case of an insufficient response, defined as a Disease Activity Score in 44 joints (DAS44) of After 1 year, mean Dutch HAQ (D-HAQ) scores were 0.7 in groups 1 and 2, and 0.5 in groups 3 and 4 (P=.009). Median increases in total Sharp/Van der Heijde radiographic joint scores were 2.0, 2.5, 1.0, and 0.5 in groups 1 through 4, respectively (P<.001). No significant differences in the number of adverse events and withdrawals were reported between the groups. 8 After 4 years of response-driven treatment, 43% of patients were in remission (DAS <1.6) and 13% were in drug-free remission, including 14%, 12%, 8%, and 18% of patients in groups 1 through 4, respectively. Significant progression of joint damage was observed in 51% and 54% of patients in groups 1 and 2, respectively, compared with 38% and 31% of patients in groups 3 and 4, respectively (P<.05, group 4 vs. groups 1 and 2; group 3 vs. group 2). 9 Based on the results of these trials, a strategy of intensive management is more effective than routine management and may actually be associated with fewer medication-related adverse events. Consistent with these findings, currently available clinical practice guidelines from both the ACR and the European League Against Rheumatism (EULAR) recommend regular patient monitoring and changes in treatment strategies until treatment goals are achieved. 10,11 Early Referral for Specialist Care 13

14 Early treatment of RA is possible only if health care professionals recognize the clinical picture of early inflammatory arthritis and accurately diagnose RA. 28 This poses a challenge in clinical practice, however, in part because there are no specific diagnostic tests for RA, and the diagnosis is based largely on signs and symptoms, which are similar to those of other inflammatory arthritides. In addition, patients may delay presentation for the treatment of joint pain. 28 The ACR 1987 classification criteria for RA are widely used in clinical practice for the diagnosis of RA (see Table 1). 29,30 These criteria were initially developed to define RA for the purpose of clinical trials, however, and thus have limited usefulness in clinical practice, with a particularly low sensitivity for early recognition of RA

15 Table 1. American College of Rheumatology 1987 Criteria for the Classification of RA 30 Criterion Definition Morning Morning stiffness in or around the affected joints lasting for stiffness Arthritis in 3 joint areas Arthritis in hand joints Symmetric arthritis Rheumatoid nodules Serum RF Radiographic changes 1 hour after initiating movement 3 joint areas simultaneously having soft tissue swelling or fluid accumulation (not bony overgrowth alone) observed by a physician (the 14 possible areas are right and left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints) 1 joint area swollen, as above, in a wrist, MCP, or PIP joint Simultaneous involvement of the same joint areas (as in criterion 2) on both sides of the body (bilateral involvement of PIP, MCP, or MTP joints is acceptable without absolute symmetry) Subcutaneous nodules over bony prominences or extensor surfaces, or in juxta-articular regions, observed by a physician Demonstration of abnormal amounts of serum RF by any method for which the result has been positive in <5% of normal control subjects Radiographic changes typical of RA on PA hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify) Note: A patient can be classified as having RA if 4 of the 7 criteria are present The first 4 criteria must be continuous for 6 weeks PIP, proximal interphalangeal; MCP, metacarpophalangeal; MTP, metatarsophalangeal; RF, rheumatoid factor; RA, rheumatoid arthritis; PA, posteroanterior. Of note, since publication of the ACR criteria, anticyclic citrullinated peptide (anti-ccp) antibodies have been shown to be highly specific for RA, and are proving beneficial for the diagnosis and classification of patients with inflammatory arthritis. They have a high sensitivity and a high specificity for RA, and a low prevalence (0.4%) in the general population. 32 However, anti-ccp antibodies are present in <60% of patients with RA. 33,34 To highlight the need for early and accurate diagnosis of RA, and initiation of DMARD therapy, specific recommendations for early referral are included in recent clinical practice guidelines. For example, 2007 EULAR recommendations note that Arthritis is characterized by the presence of joint swelling, associated with pain or stiffness. Patients presenting with arthritis of more than one joint should be referred to and seen by a rheumatologist, ideally within six weeks after the onset of symptoms. 10 Emery and colleagues have also published referral criteria based on a thorough literature review targeting early RA, early arthritis clinics, DMARD treatment for early RA, prognostic factors of disease progression, early RA clinical trials, and patient QOL. The authors noted that rapid referral to a rheumatologist is advised when RA is suspected, as supported by the presence of any of the following 35 : 15

16 3 swollen joints MTP/MCP involvement Morning stiffness lasting for 30 minutes It is important to note that normal inflammatory markers, negative serology, and normal plain radiographs are not valid reasons for delaying referral. 28 Rheumatologists must play an active role in educating both patients and health care professionals on the importance of early recognition of symptoms and referral to specialist care in cases of suspected RA. 28 Effective Treatment of RA Consistent with the paradigm of early and aggressive treatment of RA, the EULAR 2007 guidelines recommend that patients at risk for developing persistent and/or erosive arthritis be started on DMARDs as early as possible, even if they do not yet fulfill established classification criteria for inflammatory rheumatologic diseases. 10 The ACR 2002 guidelines also recommend early treatment, noting that most patients with newly diagnosed RA be started on DMARD therapy within 3 months. 11 Both traditional DMARDs (MTX, HCQ, leflunomide [LEF] and SSZ) and TNF-α antagonists (adalimumab, etanercept, and infliximab) are recommended as first-line agents for the treatment of RA Among the traditional DMARDS, MTX is considered to be the anchor drug, and should be used first in patients at risk of developing persistent disease. 10 There are no comparative RCTs among currently available TNF-α inhibitors but all appear to have similar efficacy; thus, the treatment decision depends largely on physician experience, formulary coverage, and patient preference. 13 Based on the ACR 2008 guidelines for use of biologic agents, MTX, LEF, SSZ, HCQ, and minocycline are all options for monotherapy in DMARD-naïve patients with low disease activity and without features of poor prognosis; however, it is important to note that combination therapy with traditional DMARDs is recommended initially in patients with features of poor prognosis and moderate or high disease activity. 12 The ACR 2008 guidelines recommend moving immediately to the combination of MTX plus a TNF-α antagonist for patients with high disease activity for <3 months who have features of poor prognosis. 12 Anakinra, an interleukin-1 antagonist, is also an option, but it is generally considered less effective than TNF-α antagonists and is reserved for use in patients who have failed on these agents. 13 Two additional biologic agents rituximab, an anti-b cell antibody, and abatacept, a T-cell costimulation downregulator are also indicated for use in patients who have failed treatment with TNF-α antagonists. 34,36,37 In addition to DMARDs, nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are important adjunctive therapies for relieving joint pain and inflammation, and improving joint function, in patients without gastrointestinal (GI), renal, and cardiovascular contraindications. 10,11 Systemic glucocorticosteroids can also help to reduce pain and swelling, and may be used for short-term adjunctive treatment as part of the overall DMARD strategy. Intraarticular glucocorticoid injections are preferred for the relief of local symptoms of inflammation

17 Selection of an Initial Treatment Regimen Selection of the most appropriate initial treatment regimen must be individualized, with consideration of clinical evidence, application of evidence-based guidelines, the presence of factors predicting poor prognosis, history of prior DMARD exposure, relative efficacy of the dosing regimen, dosing and route of administration preferences, concomitant medical conditions, monitoring requirements, costs of medications and monitoring, and the potential for adverse events. 11,12 Table 2 provides a summary of the dosage, onset of effect, common adverse events, and monitoring recommendations for available biologic and nonbiologic DMARDs. 13,34 17

18 Table 2. Overview of Non-biologic and Biologic DMARDs for the Treatment of RA 13,34 Drug/ Dosage Onset of Effect Adverse Events Monitoring Abatacept 500 to 1000 mg IV (weight-based) at 0, 2, and 4 weeks, then every 4 weeks 2 to 12 weeks ISR, infections, hypersensitivity, COPD exacerbation Monitor for TB, other infections; CBC, blood chemistry, and LFTs at baseline and with each Adalimumab 40 mg SC biweekly 2 to 12 weeks ISR, infections, TBr; demyelinating disorders (rare) Anakinra 100 mg SC daily 4 to 12 weeks ISR, leukopenia, infections, hypersensitivity Azathioprine 50 to 150 mg PO daily 8 to 12 weeks GI intolerance, cytopenia, hepatitis, infections Cyclosporine 2.5 to 5 mg PO daily 8 to 12 weeks GI intolerance, cytopenia, infections, hypertension, renal disease Etanercept 25 mg SC twice weekly or 50 mg SC once weekly 2 to 12 weeks ISR, infections, TBr; demyelinating disorders (rare) Hydroxychloroquine 200 to 400 mg PO daily 8 to 24 weeks GI intolerance, retinal toxicity Infliximab 3 mg/kg IV at 0, 2, and 2 to 12 weeks ISR, infections, 4 weeks, then every TBr; demyelinating 8 weeks disorders (rare) Leflunomide 20 mg PO daily 4 to 12 weeks GI intolerance, skin rash, hepatitis, cytopenia; highly teratogenic Methotrexate Minocycline Note: Minocycline is not indicated for the treatment of RA 38 [Minocycline PI/1/c3/Indications & Usage] Rituximab 15 to 25 mg PO, SC, or IM weekly 4 to 8 weeks GI intolerance, oral ulcers, alopecia, hepatitis, pneumonitis, cytopenia, rash; teratogenic 100 mg PO twice daily 4 to 12 weeks Dizziness, skin pigmentation 1000 mg IV at 0 and 15 days 2 to 12 weeks ISR, infection risk, new and infusion TB, fungal, other infections; CBC and LFTs at baseline, then every 2 to 3 months CBC at baseline and every 3 months CBC, LFTs every 2 to 4 weeks initially, then every 2 to 3 months Cr every 2 weeks at treatment initiation, then monthly; consider CBC, LFTs, and K + TB, fungal, other infections; CBC and LFTs at baseline, then every 2 to 3 months Funduscopy every 12 months TB, fungal, other infections; CBC and LFTs at baseline, then every 2 to 3 months Hepatitis B and C serology in high-risk patients; CBC, Cr, and LFTs monthly x6, then every 1 to 2 months; reduce dose or discontinue if LFTs become elevated CBC, Cr, and LFTs monthly x6, then every 1 to 2 months; reduce dose or discontinue if LFTs become elevated None Monitor for TB, other infections; CBC, blood 18

19 reactivation of viral infections, respiratory difficultly, cytopenia Sulfasalazine 2 to 3 g PO daily 4 to 12 weeks GI intolerance, oral ulcers, cytopenia, 39; Knell Gold salts 2005/78/T2-8 Usual adult dosage Initial: 10 mg IM 1 st week, 25 mg 2 nd week, then 25 to 50 mg weekly x 20 weeks or until toxicity occurs; Maintenance: 50 mg I.M. tapered progressively to every 2 to 4 weeks according to clinical response and tolerance, maintained indefinitely. Myochrysine PI 2007/7/c1/p5-7 8 to 24 weeks 39 [Myochrysine PI 2007/2/c1/p3] rash Myelosuppression, proteinuria, edema, rash, diarrhea Knell 2005/78/T2-8 chemistry, and LFTs at baseline and 2 weeks, then every 2 to 3 months thereafter CBC every 2 to 3 months CBC and urinary protein every 1-2 weeks x 20 weeks, then with every Knell 2005/78/T2-8 injection) IV, intravenous; ISR, injection-site reaction; COPD, chronic obstructive pulmonary disease; TB, tuberculosis; CBC, complete blood count; LFTs, liver function tests; SC, subcutaneous; TBr, tuberculosis reactivation; PO, orally; GI, gastrointestinal; Cr, serum creatinine; K +, potassium; IM, intramuscular. Treatment Considerations Related to Comorbidities, Potential Adverse Events, and Monitoring MTX is highly effective, and is commonly used as monotherapy and as part of combination therapy for the treatment of RA. 13 Overall, the agent is well tolerated, with between 45% and 67% of patients remaining on treatment for more than 5 to 7 years. 13 MTX use can be associated with the development of serious adverse effects, however, including bone marrow, liver, renal and pulmonary toxicities. 40 These adverse events can occur at any time during therapy, so patients should be monitored closely; this is particularly important since most adverse reactions are reversible if detected early. 40 It is also important to note that MTX elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and may require dose reduction or, in some cases, discontinuation of MTX therapy. 40 Use of oral folic acid 1 mg/day may decrease the risk for some dose-related toxicities, such as elevated liver enzymes and GI effects, that are associated with the folic acid antagonism produced by MTX. 13 Switching from an oral to an injectable dosage form may also improve GI tolerability. 13 In contrast to many of the other DMARDs, there are currently no contraindications or recommendations for routine laboratory monitoring in the labeling of TNF-α antagonists. 13,41-43 However, medically significant cytopenias (leukopenia, thrombocytopenia) have been reported infrequently and pancytopenia (including aplastic anemia) has been reported rarely with the use of TNF-α inhibitors. Therefore, all patients being treated with these agents should be instructed to report any symptoms suggestive of blood dyscrasias or infection (ie, persistent fever, bruising bleeding, and pallor). 42 Routine monitoring for infections, complete blood count (CBC), and liver function tests (LFTs) is prudent. 13,34 Rare cases of demyelinating disease have been reported with 19

20 the use of TNF-α antagonists. These agents should thus be used cautiously in patients with preexisting or recent-onset central nervous system (CNS) demyelinating disorders. 42 Infection All biologic agents are associated with an increased risk for infection (bacterial, viral, and fungal) and reactivation of tuberculosis (TB). 34 In fact, this is one of the greatest concerns regarding use of these agents. When evaluating this issue, it is important to note the following: Infections have rarely been associated with increased deaths 13 According to a study by Doran and associates, patients with RA are at increased risk for infection (objectively confirmed infections: hazard ratio (HR), 1.70; 95% CI, 1.42 to 2.03). In this study, the increased risk was shown to be associated with older age; the presence of extra-articular manifestations of RA; leukopenia; corticosteroid use; and the comorbidities of chronic lung disease, alcoholism, and diabetes mellitus. However, use of DMARDs was not associated with an increased risk for infection after adjustment for demographic characteristics, comorbidities, and disease-related variables 44 Because of the potential increased risk for serious infections in patients being treated with TNF-α antagonists, the following precautions should be taken so that such infections can be prevented, or at least readily identified and treated 45 : Evaluate the patient for infection/obtain recent travel history at each visit Evaluate the patient for respiratory and/or neurologic symptoms, fever, and constitutional symptoms Discontinue biologic agents if any signs of serious illness are present Maintain a high index of suspicion/consider coverage for unusual pathogens during serious illness Bear in mind that serious infections may present atypically, since TNF-α antagonists mediate fever, night sweats, and weight loss Treatment with TNF-α antagonists should not be initiated or should be discontinued in patients with evidence of active infection. 13 TB may be reactivated in patients receiving biologic therapy. Such patients should be screened for latent infection using the tuberculin purified protein derivative skin test or chest radiography prior to beginning therapy with biologic agents. If positive, treatment for latent TB should be initiated but does not need to be completed before beginning TNF-α antagonist therapy. If TB does develop in patients receiving treatment, it is more likely to present as disseminated infection or with extrapulmonary complications. 13 Malignancy The incidence of cancer also appears to be increased in patients with RA. Data from RCTs of biologic agents suggest the possibility of an increased risk for several types of cancer with the use of TNF-α antagonists. Although the results of observational studies indicate that there is not an increased overall risk for cancer, excess risks for certain types of cancer have been reported

21 An analysis comparing 5401 patients with RA from the Swedish Biologics Register (ARTIS) who were taking TNF-α antagonists with 67,094 control patients with RA, as well as a matched general population cohort (n=470,311), revealed the following 46 : The relative risk (RR) for cancer in patients with RA treated with TNF-α antagonists was 1.07 (95% CI, 0.74 to 1.29) The rate of cancer occurrence in the RA patient cohort not treated with TNF-α antagonist therapy corresponded to an RR of 1.09 (95% CI, 1.06 to 1.24) The adjusted RR for patients with RA treated with TNF-α antagonists vs. those who were not treated was 0.93 (95% CI, 0.76 to 1.13) Treatment with TNF-α antagonists was associated with a reduced risk for breast cancer (RR=0.48; 95% CI, 0.28 to 0.84) compared with no treatment. The use of TNF-α antagonists was associated with an increased risk, although not significant, for colorectal cancer (RR=1.52; 95% CI, 0.85 to 2.78; n=14); nonmelanoma skin cancer (RR=1.55; 95% CI, 0.76 to 3.15; n=10); and CNS cancer (RR=2.25; 95% CI, 0.81 to 6.25; n=5) It is recommended that patients with RA, particularly those treated with TNF-α antagonists, undergo age-appropriate screening for malignancy. 34 Cardiovascular Disease and Congestive Heart Failure Systemic inflammation appears to lead to an increased risk for cardiovascular disease in patients with RA. Effectively targeting this inflammation early on appears to provide cardiovascular benefits. 47,48 In one study, rates of myocardial infarction (MI) were compared in 8670 patients with active RA treated with TNF-α antagonists with rates in 2170 patients with active RA treated with traditional DMARDs. 47 Based on these data from the British Society for Rheumatology Biologics Register, 63 MIs occurred during 13,233 person-years of follow-up in patients treated with TNF-α antagonists, vs. 17 MIs in the DMARD cohort during 2893 person-years of follow-up. This was equivalent to a rate of 4.8 events per 1000 person-years and 5.9 events per 1000 person-years, respectively. 47 Although there was no reduction in the rate of MI in the TNF-α antagonist cohort vs. the DMARD cohort (incidence rate ratio, 1.44; 95% CI, 0.56 to 3.67) after adjustment for baseline risk factors, a subanalysis of patients who responded to TNF-α antagonist therapy within 6 months reported lower MI rates compared with nonresponders (3.5 events per 1000 personyears vs. 9.4 events per 1000 person-years, respectively; adjusted incidence rate ratio, 0.36; 95% CI, 0.19 to 0.69). 47 Interestingly, the results of another study also demonstrated possible survival benefits among patients treated with MTX, including a significant reduction in the risk for cardiovascular mortality. 13,49 These data lend additional support to the preponderance of evidence endorsing effective attenuation of inflammation in patients with RA. Similarly, a study including data from the German biologics register in RA patients 18 to 75 years of age who started treatment with infliximab, etanercept, or adalimumab (n=2757), or conventional DMARDs (controls; n=1491), showed that TNF-α inhibitor treatment that effectively reduces the inflammatory activity of RA is more likely to be beneficial than harmful with respect to risk for heart failure. 50 This was particularly true in patients who were not receiving concomitant therapy with glucocorticoids or COX-2 inhibitors. The results of the study were as follows 50 : 21

22 The 3-year incidence rates of heart failure in patients with and those without cardiovascular disease at initiation of treatment were 2.2% and 0.4%, respectively After adjustment for traditional cardiovascular risk factors, an increased risk for the development of heart failure was reported among patients who had a higher DAS28 at follow-up (HR, 1.47; 95% CI, 1.07 to 2.02; P=.019) A residual nonsignificant risk associated with TNF-α inhibitor treatment remained (adjusted HR, 1.66; 95% CI, 0.67 to 4.1; P=.28). This residual risk was balanced by the efficacy of the anti-tnf therapy When only baseline characteristics were considered, the HR related to TNF-α inhibitor use decreased to 0.70 (95% CI, 0.27 to 1.84) In contrast, the results of a Medicare database cohort study of RA patients 65 years of age who were treated with TNF-α antagonists (n=1002) or MTX (n=5593) revealed the following 51 : There were 59 hospital admissions for heart failure during 1680 person-years of TNF-α antagonist use and 227 heart failure admissions during 10,623 person-years of MTX use The adjusted HR for heart failure hospitalization was 1.70 (95% CI, 1.07 to 2.69) for TNF-α antagonists vs. MTX, with similar results reported in patients with and without prior heart failure Current labeling for TNF-α antagonists in patients with heart failure includes cautions with etanercept and adalimumab use, 41,42 and a contraindication for infliximab use in patients with moderate to severe heart failure. 43 Until additional data become available, it is prudent to use these agents cautiously, if at all, in this patient population, particularly in those who are elderly 51 and/or have more severe heart failure. 12 Osteoporosis Patients with RA have an increased risk for osteoporosis. 52,53 Therefore, screening for osteoporosis and preventive measures, including treatment with calcium 1000 mg/day plus vitamin D 400 to 800 IU/day in adults <50 years of age and calcium 1200 mg/day plus vitamin D 800 to 1000 IU/day in adults 50 years of age, are mandatory. 54 In addition, physicians should exercise a low threshold for use of antiresorptive agents in such patients. 52 Recommendations regarding contraindications to initiating or resuming therapy with biologic and nonbiologic DMARDs in patients with RA are summarized in Table 3. 22

23 Table 3. Contraindications to Initiating or Resuming DMARD Therapy in Patients With RA 12,a a The presence of a dash does not indicate an affirmative recommendation for use of the agent in a particular clinical circumstance. b TB treatment and full adherence as recommended by TB expert and considered successfully treated. c Felty s syndrome and large granular lymphocyte syndrome as causes of neutropenia are possible exceptions. d NYHA class III=patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. NYHA class IV=patients with cardiac disease resulting in the inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. 23

24 e Therapy defined as antiviral regimen deemed appropriate by expert in liver diseases. f The Child-Pugh classification liver disease scoring system is based on the presence of albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Patients with a score 10 (in the class C category) have a prognosis with 1-year survival of ~50%. Patients with class A or B have a better prognosis of 5 years, with a survival rate of 70% to 80%. g Contraindicated for Child-Pugh class C only. DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis; ABA, abatacept; anti-tnf-α, anti tumor necrosis factor-α; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; MIN, minocycline; RIT, rituximab; SSZ, sulfasalazine; X, contraindication; TB, tuberculosis; NYHA, New York Heart Association. Table 4 summarizes recommendations for the management of patients with RA and common comorbidities. Table 4. Comorbidities in Patients With RA: Summary of Disease-Specific Risk Factors and Preventive Measures 45,48,55 Comorbidity General Risk Factors RA-Specific Risk Factors Preventive Measures Cardiovascular Disease 45,52 Known cardiovascular disease Dyslipidemia Hypertension Smoking Diabetes Hyperhomocysteinemia Family history Male gender Advanced age Malignancy 45 Smoking Family history Others Severe long-standing disease (elevated inflammatory markers such as CRP) MTX (± SSZ) Glucocorticoid use NSAID use Severe long-standing disease Immunosuppressive therapy Sjögren s syndrome Lifestyle modifications, including diet, exercise, and and smoking cessation Treatment of hypertension, dyslipidemia, and diabetes Folate supplementation in MTX users Anti-inflammatory measures aimed at lowering CRP levels (?) HCQ (?) Minimize glucocorticoid exposure Routine surveillance by history and physical exam, as well as hematologic studies Minimize immunosuppressive exposure Infection 42,45 Known immunodeficiency state Severe long-standing disease Immunosuppressive therapy Routine influenza and pneumococcal vaccinations Routine surveillance Maintain high index of suspicion/consider coverage for unusual pathogens 24