rheuma conference hilights hires 02 13

CONFERENCE HIGHLIGHTS

A CME-Certifi ed Supplement to

Rheumatology News®

Family Practice News®

Internal Medicine News®

JOINT SPONSORSHIP: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Louisville School of Medicine and Global Academy for Medical Education, Inc. The University of Louisville School of Medicine is accredited by the ACCME to provide continuing education for physicians.DESIGNATION STATEMENT: The University of Louisville School of Medicine designates this educational ac-tivity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.TARGET AUDIENCE: This activity has been designed for rheumatologists, primary care physicians, and other health care providers who treat patients with rheumatic diseases.STATEMENT OF NEED: Improved understanding of the molecular biological basis of rheumatologic disorders has led to the development of diagnostic and therapeutic strate-gies that have enhanced disease management and patients’ quality of life. Nonetheless, challenges remain in the quest for optimal disease control of conditions such as rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis (PsA).Challenges to better management of RA include the need for appropriate and accurate ongoing assessment of disease status and response to therapy. Multiple assessment instruments have been developed, and each provides useful but diff erent clinical information about patients with RA. By recognizing the similari-ties and diff erences among these tools, clinicians can apply the assessments that yield the most useful information about the patient population in specifi c clinical practice settings.The advent of biologic therapy has greatly improved the management of psoriasis. In particular, inhibitors of tumor necrosis factor have become a cornerstone of therapy for RA, PsA and psoriasis. Advances in basic science have led to the development of new biologic approaches to the treatment of these diseases, and clinicians will be challenged to remain abreast of the options and how to use the therapies to the greatest benefi t of patients.LEARNING OBJECTIVES: After reading and study-ing this supplement, participants should be able to:• Evaluate the safety, effi cacy, and applicability of available

therapies for RA in their own clinical practices• Recognize mechanistic diff erences in currently available

therapies for RA, psoriasis, and PsA• Identify advances shown in recent clinical studies of biologics• Describe assessment tools for evaluating disease status and

response to therapy in patients with RA• Recognize comorbidities that often occur in patients with

psoriasis and PsA and appreciate the need to manage these comorbid conditions, as well as the rheumatologic condition

5TH ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES

TM

T he fi eld of rheumatology has evolved dramatically in recent years as im-proved understanding about the un-

derlying mechanisms of rheumatic diseases has driven development of new therapies and therapeutic strategies. Clinicians can of-fer patients more options, many of which were not available just a few years ago.

Increasingly, the challenge to rheuma-tologists and other clinicians involved in treating rheumatic diseases is to integrate new information and therapeutic strate-gies into clinical practice. This supplement to Rheumatology News, developed from se-lect presentations given at the 5th Annual

Perspectives in Rheumatic DiseasesTH confer-ence—presented by Rheumatology News, Family Practice News and Internal Medicine News, and held September 28 and 29, 2012, in Newport, California—offers a concise account of recent developments in the management of selected rheumatic diseas-es. The information focuses on key aspects of patient management that are readily ap-plicable to clinical practice.

The information refl ects current knowl-edge, standards, and practices in rheumatic diseases. We hope that readers will fi nd the summaries informative and readily appli-cable to clinical practice.

Optimal clinical management of rheumatoid arthritis (RA) requires accurate assessment of disease

activity and timely, appropriate therapeutic intervention to maintain disease control. Effective ongoing disease management has acquired a greater sense of urgency with the recognition that joint erosions occur early in the course of RA. More than 90% of patients have radiographic abnormali-ties within 2 years of diagnosis.1,2

As knowledge about the underlying causes of RA has increased, so have the therapeutic options. Patients benefi t from the availability of multiple treatment op-

tions, but the expanding armamentarium also complicates therapeutic decision mak-ing. The success of therapeutic strategies depends on a clinician’s ability to integrate information from multiple sources, to rec-ognize the value and the limitations of that information, and to apply the information to optimize patient outcomes.

Accurate Clinical AssessmentThe American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have agreed upon new diagnostic criteria for RA (Figure).3 The criteria comprise clinical and laborato-

You Just Made the Diagnosis of RA: What Do You Do Now?

Daniel E. Furst, MD, Conference ChairCarl M. Pearson Professor of MedicineDepartment of Medicine, Division of RheumatologyDavid Geff en School of Medicine at the University of California, Los Angeles

Jointly sponsored by:

and

This activity is supported by educational grants from:

Original Release Date: February 28, 2013Most Recent Review Date: February 2013Expiration Date: February 28, 2014Estimated Time to Complete Activity: 1.0 hoursMedium or Combination of Media Used: Written SupplementMethod of Physician Participation: Journal Supplement To get instant CME credit online, go to http://uofl .me/prd13

2 globalacademycme.com/rheumatology • 5th Annual Perspectives in Rheumatic Diseases

ry fi ndings developed to guide clinicians in the differential diagnosis and classifi cation of new patients and to make that diagnosis earlier in the disease course. The guidelines have reasonable sensitivity for RA but lack specifi city.

Investigators in a recent study evaluated the specifi city of the ACR/EULAR crite-ria in 112 patients with established rheu-matologic diagnoses.4 The results showed that 96.7% of patients with RA met the diagnostic criteria. However, so did 66.7% of patients with systemic lupus erythema-tosus, 50% of those with osteoarthritis, and 37.5% of those with psoriatic arthritis.

Assessment ToolsTo guide decision making, clinicians can rely on a variety of clinical parameters and assessments, including joint counts, pa-tient and physician global assessments, the Health Assessment Questionnaire (HAQ), laboratory values, and categorical outcome measures, such as ACR response. In re-cent years, multiple continuous assessment tools have been developed and refi ned, such as the Disease Activity Score (DAS), the Simplifi ed Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI).

Multiple studies have shown that close monitoring and repeated application of outcome measures to drive treatment deci-sions lead to better outcomes in RA. Ap-preciating the strengths and limitations of currently available assessment tools can help clinicians use those tools to maximize the benefi t for patients.

The 28-joint DAS (DAS28) and the 44-joint version of the instrument have been validated as a refl ection of disease activity and extent of joint involvement in RA. The principal caveat regarding use of the DAS relates to interpretation of the score. A low DAS does not mean absence of disease, but rather low disease activity.

The SDAI comprises fi ve measures: ten-der and swollen joint count, Patient’s Global Assessment (PGA), Physician’s Global As-sessment, and C-reactive protein (CRP) or erythrocyte sedimentation rate levels.

The SDAI has good correlation with the Health Assessment Questionnaire Dis-ability Index (HAQ-DI), DAS28, and ACR response. The CDAI simplifi es offi ce as-sessment by eliminating the laboratory (CRP) component of the SDAI. This in-dex correlates well (~90%) with the SDAI and DAS28.5

The Routine Assessment of Patient In-dex Data (RAPID)-3 combines three types

of information: Modifi ed HAQ-DI (an 8-question version of the HAQ-DI), pa-tient-reported pain, and the PGA. The in-strument relies entirely on patient-report-ed information, which can be provided on a single questionnaire in the waiting room.

In large part, the RAPID-3 has gained support in the rheumatologic community because of its virtual elimination of clini-cian time commitment. However, the in-strument has relatively poor correlation with the DAS28 and the CDAI (only ~73% for either), both of which provide impor-tant information about disease status.6

Treating to TargetClinical targets have been widely used in disease management: hypertension, dyslip-idemia, and diabetes, to name a few. For each condition, clinicians have well-recog-

ACKNOWLEDGMENTS: The authors would like to thank Global Academy for Medical Education and Charles Bankhead for assistance with the preparation of this supplement.DISCLOSURE: As a sponsor accredited by the ACCME, CME&PD must ensure balance, independence, objectivity, and scientifi c rigor in all its sponsored educational activities. All faculty participating in this CME activity were asked to disclose the following: 1. Names of proprietary entities producing health care goods

or services—with the exemption of nonprofi t or government organizations and non–health-related companies—with which they or their spouse/partner have, or have had, a relevant fi nancial relationship within the past 12 months. For this purpose, we consider the relevant fi nancial rela-tionships of a spouse/partner of which they are aware to be their fi nancial relationships.

2. Describe what they or their spouse/partner received (eg, salary, honorarium).

3. Describe their role.3. No relevant fi nancial relationships.Jennifer C. Cather, MD, has been a consultant and/or in-vestigator and/or speaker for Abbott, Amgen, Celgene, Janssen Biotech, Novartis, and Pfi zer.Daniel E. Furst, MD, has been a consultant for Abbott, Actelion, Amgen, Biogen Idec, Bristol-Myers Squibb, Janssen Biotech, Corronna, Genentech, Gilead, GlaxoSmithKline, National Institutes of Health, Novartis, Pfi zer, Roche, and UCB.Joel M. Kremer, MD, has been a consultant and/or speaker for Abbott, Amgen, Bristol-Myers Squibb, Genentech, and Pfi zer.Christopher T. Ritchlin, MD, MPH, has been an investi-gator and/or consultant for Amgen, Janssen Biotech , Pfi zer, and UCB.Sylvia Reitman, MBA, has no relevant fi nancial relation-ships with any commercial interests.Charles Bankhead has no relevant fi nancial relationships with any commercial interests.TO OBTAIN CME CREDIT: To get instant CME credits online, go to http://uofl .me/prd13. Upon successful comple-tion of the online test and evaluation form, you will be direct-ed to a Web page that will allow you to receive your certifi cate of credit via e-mail. Please add cmepd@louisville.edu to your e-mail “safe” list. (Type the above address into your address bar in Internet Explorer. If you are unfamiliar with what an address bar is or how to access yours, open Internet Explorer, then hold down the control key and press the “O” key on your keyboard. A dialogue box will open—this is where you will type the above address. After you have typed the address, click OK to go to the evaluation.) Once you have completed the evaluation, it will give you a password. Please be sure to write it down; you will then be able to access your certifi cate. Please note, certifi cates will not be mailed, so be sure to print a copy for your records. If you have any questions or diffi culties, please contact the University of Louisville School of Medicine Continuing Medical Education offi ce at cmepd@louisville.edu

continued on page 7

• ≥1 joint with synovitis (excluding the DIP, fi rst MTP, and fi rst CMC joints)

• Absence of alternative diagnosis that better explains synovitis

• Achievement of total score of ≥6 (of 10) from individual scores in 4 domains~Joint involvement patterns~Serologic abnormality ~Elevated acute-phase response~Symptom duration

Swollen/Tender Joints (0-5)1 large joint 02-10 large joints 11-3 small joints 24-10 small joints 3>10 joints (≥1 small joint) 5Serology (0-3)Negative RF and ACPA 0Low-positive RF or ACPA 2High-positive RF or ACPA 3Symptom Duration (0-1)<6 weeks 0 ≥6 weeks 1Acute-Phase Reactants (0-1)Normal CRP and normal ESR 0Abnormal CRP or abnormal ESR 1

Patients with a score of ≥6 have “defi nite” RA

RA=rheumatoid arthritis; ACR=American College of Rheumatology; EULAR=European League Against Rheumatism; DIP=distal interphalangeal joint; MTP=metatarsophalangeal; CMC=carpometacarpal; ACPA=anti-citrullinated protein antibody; RF=rheumatoid factor; CRP=C-reactive protein; ESR=erythrocyte sedimentation rate

Source: Adapted from Aletaha D et al.3

Figure. 2010 ACR/EULAR RA Classifi cation Criteria

REGISTER NOW6th Annual Perspectives in

Rheumatic DiseasesTM a continuing medical education conference

September 20-21, 2013Mandalay Bay Hotel, Las Vegas

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5th Annual Perspectives in Rheumatic Diseases • globalacademycme.com/rheumatology 3

Direct comparisons of therapies provide valuable clinical infor-mation, but remain all too un-

common in some fi elds of medicine. The fi eld of rheumatology has benefi ted from recent expansion of therapeutic options for rheumatoid arthritis (RA), but, until recently, no clinical trials had directly com-pared newer agents against one another. At the 2012 meeting of the European League Against Rheumatism (EULAR), two pre-sentations attracted considerable atten-tion because they represented the rarest of clinical trials: randomized comparisons of different biologic therapies for RA. The results have potential to infl uence clinical practice regarding management of patients with RA.

Anti-interleukin 6 vs TNF InhibitorThe ADACTA (ADalimumab ACTemrA) trial compared a member of the widely used tumor necrosis inhibitor (TNF) class of biologic therapies (adalimumab) and a new entry into the fi eld of RA, the anti-interleukin (IL)-6 antibody tocilizumab.1 Eligible patients had an RA duration ≥6 weeks, 28-joint Disease Activity Score (DAS-28) >5.1, at least six swollen joints, eight or more tender joints, an erythro-cyte sedimentation rate >28 mm/h or C-reactive protein level ≥1 mg/dL, and no history of treatment with a biologic agent.

Investigators at sites in Europe and the United States randomized patients 1:1 to intravenous tocilizumab 8 mg/kg every 4 weeks plus subcutaneous placebo admin-istered every 2 weeks or to subcutaneous adalimumab 40 mg every 2 weeks plus an intravenous placebo once every 4 weeks. Follow-up continued for 24 weeks, and the primary endpoint was the change from baseline in DAS28 score, which was as-sessed every 4 weeks.

The study involved 326 patients, all but one of whom were included in the data analysis. Demographic and baseline clinical characteristics did not differ signifi cantly between the treatment groups.

Primary OutcomesThe primary analysis demonstrated a

3.3-point decline in mean DAS28 score in the tocilizumab arm compared with 1.8 in the adalimumab group, a statistically signif-icant difference in favor of the IL-6 inhibi-tor (P<0.0001) (Figure). A difference in DAS28 favoring tocilizumab emerged af-ter 4 weeks, continued to increase to about 12 weeks, and then remained stable in both groups until week 24.

Key secondary endpoints of the trial in-cluded DAS28 remission (<2.6) or low dis-ease activity (≤3.2) at 24 weeks. The results showed that 51.5% of the tocilizumab group achieved low disease activity and 39.9% met the defi nition for remission. That compared with a remission rate of 10.5% and low dis-ease activity in 19.8% of patients random-ized to adalimumab (P<0.0001 vs tocili-zumab for both outcomes).

Investigators also assessed the propor-tion of patients in each group who met American College of Rheumatology (ACR) response criteria. The results showed a sig-nifi cant advantage for the tocilizumab arm with respect to ACR20 response (65.0% vs 49.4%, P<0.005), ACR50 (47.2% vs 27.8%, P<0.0005), and ACR70 (32.5% vs 17.9%, P<0.005).

A post hoc analysis showed that almost twice as many patients in the tocilizumab group met Clinical Disease Activity Index (CDAI) criteria for remission (≥0 to ≤2.8) at the 24-week follow-up visit (17.2% vs 9.3%, P=0.0389). Analysis of data on CDAI low disease activity (≤10) also fa-vored tocilizumab treatment (30.7% vs

29.0%), resulting in a signifi cant advantage for CDAI remission/low disease activity combined (P=0.0003).

SafetyAnalysis of safety data showed that the groups had similar rates of adverse events, serious adverse events, and infections. Two deaths occurred in the tocilizumab group: one resulting from illicit drug use and one sudden death involving a patient who had a history of cardiovascular and pulmonary disease.

The ADACTA trial was statistically powered to demonstrate superiority of to-cilizumab versus adalimumab, and the re-sults confi rmed the superiority hypothesis. The safety profi le was similar in the two groups, and no new or unexpected adverse events occurred in either group.

Add-On Biologic TherapyIn contrast to the ADACTA trial, the Abatacept Versus Adalimumab Compari-son in Biologic-Naïve Rheumatoid Arthri-tis Subjects With Background Methotrex-ate (AMPLE) study involved patients with RA currently treated with methotrexate.2 The trial was the fi rst to compare two biologic agents in patients whose RA had not responded adequately to methotrex-ate. The trial was statistically powered to demonstrate noninferiority of abatacept (a fusion-protein construct that inhibits

At the Cutting Edge: Newest Data on RA TherapyJoel M. Kremer, MDPfaff Family Professor of Medicine,Albany Medical CollegeDirector of Research, The Center for RheumatologyAlbany, NY

continued on page 5

ADA 40 mg SC+ IV Placebo TCZ 8 mg/kg IV+ SC Placebo

n 162 163Adjusted mean -1.8 -3.3Diff erence -1.595% CI for diff erence -1.8 to -1.1P value <0.0001

Table. ADACTA Primary Endpoint: Change in DAS28 From Baseline to Week 24 (ITT Population)*

*Analysis of variance (model included baseline value plus the stratifi cation factors of region and duration of rheumatoid arthritis. One ADA patient did not receive treatment; 2 TCZ patients had no postbaseline data. LOCF was used for missing TJC, SJC, ESR, and Patient’s Global VAS. If ESR=0, then ESR=1 was substituted into the DAS28 calculation to enable a nonmissing DAS28. ADACTA=ADalimumab ACTemrA; DAS28=28-joint Disease Activity Score; ITT=intent to treat; ADA=adalimumab; SC=subcutaneous; IV=intravenous; TCZ=tocilizumab; CI=confi dence interval; LOCF=last observation carried forward; TJC=tender joint count; SJC=swollen joint count; ESR=erythrocyte sedimentation rate; VAS=visual analog scaleSource: Gabay C et al.1

4 globalacademycme.com/rheumatology • 5th Annual Perspectives in Rheumatic Diseases

Improved understanding of psoriatic arthritis (PsA) has led to the recog-nition that the condition confers ad-

verse effects similar to those more closely associated with rheumatoid arthritis (RA): joint destruction, functional and work disability, treatment-related side effects, psychosocial dysfunction, and reduced quality of life and life expectancy.1 Also similar to RA, PsA has associations with a broad spectrum of musculoskeletal manifestations.

Unlike individuals with RA, many pa-tients with PsA also develop psoriasis and related psoriatic comorbidities: nail dis-ease, obesity, hypertension, type 2 diabetes, hyperlipidemia, steatosis, metabolic syn-drome, myocardial infarction, and anxiety/depression. Between 10% and 15% of pa-tients develop infl ammatory bowel disease. The constellation of comorbidities and disease manifestations has been character-ized as the psoriatic march, which begins

with obesity, psoriasis, smoking, and/or alcohol consumption (Figure 1).2 Those factors induce and maintain systemic in-fl ammation, leading to insulin resistance, endothelial dysfunction, atherosclerosis, and myocardial infarction.

The multicentric nature of PsA requires a comprehensive approach to evaluation and treatment that addresses musculoskel-etal and skin manifestations, risk factors for diabetes and cardiovascular disease, and the psychoemotional effects of the condition. A comprehensive approach re-quires close collaboration between rheu-

matologists and dermatologists, as well as patients’ primary care physicians.

Evaluation of the Patient With PsAConventional assessment tools for patients with RA have little value in the evaluation of patients with PsA. For example, the 28-joint Disease Activity Score (DAS28) often fails to identify signifi cant disease burden in patients with PsA because the disease is distal interphalangeal predomi-nant or has substantial involvement of the feet. Characterizing the true extent of disease burden in PsA may require assess-ment of 66/68-joint activity, which is time consuming but provides a more accurate clinical picture of the patient.

Enthesitis is a common fi nding in PsA and might involve multiple sites, including the supraspinatus, lateral epicondyle, iliac crest, trochanter, patellar/quadriceps, and plantar fascia/Achilles tendon. The evalu-ation requires relatively little time and usu-

ally is quite informative about the extent of tenderness and infl ammation.

In contrast to the traditional goal of remission in RA, the treatment goal in PsA focuses on attainment of minimal dis-ease activity (MDA). MDA cri-teria encompass a clinical spec-trum that includes tender and swollen joints, extent of body surface area involvement or ex-tent of clearance, pain, global activity, disability, and tender points (Figure 2).3

Assessing Therapies and ResponseThe Group for Research and Assess-

ment of Psoriasis and Psoriatic Arthritis (GRAPPA) has developed evidence-based guidance for use of therapeutic interven-tions in PsA.4 The approach encompasses the fi ve domains that require consideration in the development of an effective treat-ment plan: peripheral arthritis, skin and nail disease, axial disease, dactylitis, and enthesitis. Examination of the GRAPPA approach shows that most interventions have demonstrated effects on one or two domains. Only biologic agents, specifi cally

tumor necrosis factor (TNF) inhibitors, have been shown to affect the status of all fi ve domains of PsA.

Identifying the best therapeutic option for a patient with PsA is complicated by the lack of useful biomarkers of disease activity, such as rheumatoid factor, anti-citrullinated peptide antibodies, or antinuclear antibod-ies, all of which are used to assess disease activity in RA. Instead, clinicians often base therapeutic choices on the sum of consid-erations that can infl uence the choice: effi -cacy in joints and skin, risk of progression, quality-of-life issues, safety, mode of admin-istration, and economic realities.

Clinicians do have some evidence to help them identify patients who are likely to prog-ress on therapy.5-7 The clues include absent or inadequate response to initial therapy, a history of treatment with corticosteroids, number of involved joints, joint erosions on x-ray, elevated markers of infl ammation, sex (women at higher risk), and clinical sub-group (peripheral disease at higher risk than oligoarticular and axial disease).

More recently, obesity has emerged as a potential predictor of therapeutic response. Studies reported at the 2012 meeting of the European League Against Rheumatism (EULAR) showed that pa-tients who achieved MDA had a signifi -cantly lower prevalence of obesity and that weight loss improved a patient’s odds of achieving MDA during treatment with TNF inhibitors.8,9

Psoriatic Arthritis: Maximizing Patient OutcomesChristopher Ritchlin, MD, MPHProfessor of MedicineDirector, Translational Immunology Research CenterUniversity of Rochester Medical CenterRochester, NY

Patients are classifi ed as in MDA when they meet 5 of 7 of the following criteria: • Tender joint count ≤1• Swollen joint count ≤1• PASI ≤1 or BSA ≤3• Patient pain VAS ≤15• Patient global activity VAS ≤20• HAQ ≤0.5• Tender entheseal points ≤1PASI=Psoriasis Area and Severity Index; BSA=body surface area; VAS=visual analog scale; HAQ=Health Assessment QuestionnaireSource: Coates L et al.3

Figure 2. Criteria for Minimal Disease Activity (MDA)

Systemic inflammation

Insulin resistance

Endothelial dysfunction

Atherosclerosis

Myocardial infarction

Obesity

Psoriasis

Smoking/alcohol

= association

Figure 1. The Psoriatic March

Source: Adapted from Boehncke WH et al.2

5th Annual Perspectives in Rheumatic Diseases • globalacademycme.com/rheumatology 5

signaling associated with T-cell activation) versus adalimumab.

Investigators in the United States, the Netherlands, and Argentina randomized 646 patients with active RA despite metho-trexate therapy to subcutaneous abatacept 125 mg weekly or to subcutaneous adali-mumab 40 mg every 2 weeks. Treatment and follow-up continued for a year, and the primary endpoint was the proportion of patients who met ACR20 response criteria.

As in the ADACTA study, baseline char-acteristics did not differ notably between treatment groups. The patients had a medi-an RA duration of almost 2 years, refl ect-ing a longer treatment history than that of the ADACTA study population.

The results showed that 64.8% of pa-tients in the abatacept arm met criteria for ACR20 response, as did 63.4% of patients in the adalimumab arm. The 1.4% absolute difference between groups (1.8% adjusted estimate) was not statistically signifi cant, but fell without the statistical limits for non-inferiority, thus meeting the primary end-

point of the trial. Examination of ACR20, ACR50, and ACR70 response rates over the year of treatment showed similar rates in the two groups at all time points.

The DAS28 response rates included re-mission in 43.3% and 41.9% of patients in the abatacept and adalimumab groups, respectively, and low disease activity in 59.3% and 61.4% of patients, respectively. Neither outcome differed signifi cantly be-tween the groups, and both drugs dem-onstrated comparable inhibition of radio-graphic progression.

Similarity between the two groups con-tinued with the safety data, which showed no differences in adverse events, serious ad-verse events, or infections. Discontinuation due to adverse events occurred slightly less often with abatacept, as did injection-site re-actions. One sudden cardiac death occurred in the abatacept arm and involved a 66-year-old man with a history of hypertension.

SummaryTwo recent clinical trials have provided

much-needed data regarding head-to-head comparisons of biologic agents for RA. One trial demonstrated superiority of tocilizumab versus adalimumab for re-ducing the DAS28 score, including remis-sion and low disease activity. The other trial showed that abatacept and adalim-umab had similar effi cacy, as defi ned by the proportion of patients who attained ACR20 responses during a year of treat-ment and follow-up. Results of these tri-als offer clinical guidance to clinicians who treat patients with RA.

References1. Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab

monotherapy is superior to adalimumab monotherapy in reducing disease activity in patients with rheumatoid arthritis: 24-week data from the phase IV ADACTA trial. Presented at: Annual Meeting of the European League Against Rheumatism; June 6-9, 2012; Berlin, Germany. Abstract LB0003.

2. Schiff M, Fleischmann R, Weinblatt M, et al. Abatacept SC versus adalimumab on background methotrexate in RA: One-year results from the AMPLE study. Presented at: Annual Meeting of the European League Against Rheu-matism annual; June 6-9, 2012; Berlin, Germany. Abstract OP0022.

Therapeutic OptionsMethotrexate, a mainstay of treatment for RA, has little supporting evidence in PsA. The drug has been evaluated in only one randomized trial of patients with PsA.10 The trial was relatively small, and a con-siderable number of patients dropped out before the end of the study. However, the results showed no signifi cant effect of methotrexate on the primary endpoint (Psoriatic Arthritis Response Criteria) or key secondary outcomes (American Col-lege of Rheumatology [ACR] response, DAS28, swollen/tender joint counts, and proinfl ammatory markers).

In contrast to methotrexate, TNF inhib-itors have become a mainstay of therapy for PsA. With relative consistency, studies have shown MDA rates of 40% to 45% with different TNF inhibitors.11 At the 2012 EULAR meeting, data from a clinical trial of certolizumab pegol showed Psoria-sis Area and Severity Index score improve-ments of 60% and 75% at 24 weeks, as well as ACR20/50/70 responses.12

Patients who have inadequate or no response to TNF inhibitors have several options.13 They include treating the site of fl are and/or optimizing use of non-steroidal anti-infl ammatory drugs; adding

or switching to a disease-modifying drug or a different TNF inhibitor; switching to ustekinumab; or trying another drug such as abatacept, prednisone, cyclosporine, or azathioprine (alone or in combination).

SummaryPsA and RA have some clinical features in common but also differ in many respects, including clinical manifestations, thera-peutic options, and response to therapy. Patients with PsA require a comprehensive approach to clinical management, begin-ning with early diagnosis and treatment. Rheumatologists, dermatologists, and pri-mary care physicians must collaborate to afford patients the greatest opportunity for optimal outcomes. Careful selection and timing of therapy are essential to good outcomes.

References 1. Kalden JR. How do the biologics fi t into the current

DMARD armamentarium? J Rheumatol. 2001;28(suppl 62):27-35.

2. Boehncke WH, Boehncke S, Schön MP. Managing comorbid disease in patients with psoriasis. BMJ. 2010;340:b5666.

3. Coates L, Fransen J, Helliwell PS. Defi ning minimal dis-ease activity in psoriatic arthritis: A proposed objective target for treatment.Ann Rheum Dis. 2010;69: 48-53.

4. Kavanaugh AF, Ritchlin CT; GRAPPA Treatment Guide-

line Committee. Systematic review of treatments for psoriatic arthritis: An evidence-based approach and basis for treatment guidelines. J Rheumatol. 2006;33:1417-1421.

5. Gladman DD, Farewell VT, Nadeau C. Clinical indica-tors of progression in psoriatic arthritis: Multivariate relative risk model. J Rheumatol. 1995;22:675-679.

6. Gladman DD, Farewell VT, Wong K. Husted J. Mortality studies in psoriatic arthritis: Results from a single outpa-tient center. II. Prognostic indicators for death. Arthritis Rheum. 1998;41:1103-1110.

7. Gladman DD, Farewell VT. Progression in psoriatic arthritis: Role of time varying clinical indicators. J Rheumatol. 1999;26:2409-2413.

8. Di Minno MND, Peluso R, Iervolino S, et al. Obesity and the prediction of the minimal disease activity: A prospec-tive study in psoriatic arthritis patients. Presented at: Annual Meeting of the European League Against Rheumatism; June 6-9, 2012; Berlin, Germany. Abstract OP0162.

9. Di Minno MND, Iervolino S, Peluso R, et al. Weight loss and induction of minimal disease activity in psoriatic arthritis patients starting TNF-α blockers treatment. Presented at: Annual Meeting of the European League Against Rheumatism; June 6-9, 2012; Berlin, Germany. Abstract OP0163.

10. Kingsley GH, Kowalczyk A, Taylor H, et al. A random-ized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012;51:1368-1377.

11. Mease PJ. Psoriatic arthritis: Update on pathophysiol-ogy, assessment, and management. Ann Rheum Dis. 2011;70(suppl 1):i77-i84.

12. Mease PJ, Fleischmann R, Deodar A, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a phase 3 double-blind randomized placebo-controlled study (RAPID-PSA). Presented at: Annual Meeting of the European League Against Rheumatism; June 6-9, 2012; Berlin, Germany. Abstract LB0001.

13. Ritchlin CT. Therapeutic considerations in spondylarthri-tis patients who fail tumour necrosis factor antagonists. Best Pract Res Clin Rheumatol. 2010;24:683-692.

At the Cutting Edge: Newest Data on RA Therapy continued from page 3

6 globalacademycme.com/rheumatology • 5th Annual Perspectives in Rheumatic Diseases

The conceptual framework under-lying the etiology of psoriasis has undergone dramatic transforma-

tion in recent years. Recognition of the immunologic and infl ammatory processes that drive the condition has led to the development of therapies that more spe-cifi cally address those processes. Therapy focused primarily on the dermatologic manifestations of the disease has given way to treatment that offers the potential to modify the biologic drivers.1

Increased recognition of the systemic nature of psoriasis also has led to appre-ciation of the diversity of adverse effects associated with the condition: arthritis, liver disease, diabetes and metabolic syn-drome, obesity, cardiovascular disease, depression, and infl ammatory bowel dis-ease. Moreover, psoriasis exacts a heavy quality-of-life toll, disrupting sleep, am-bulation, manual dexterity, and the abil-ity to sit or stand for prolonged periods. The cumulative effects of psoriasis lead to disability that meets or exceeds that of major conditions more commonly associ-ated with disability, including congestive heart failure, chronic lung disease, diabe-tes, arthritis, and myocardial infarction, among others.2 The economic impact of psoriasis cannot be overlooked. For many patients, psoriasis leads to substantial ab-senteeism from work and reduced pro-ductivity at work.

By targeting the underlying biologic pro-cesses of psoriasis, modern therapies af-ford greater opportunity to minimize the cosmetic, systemic, emotional, social, and economic effects of the condition.

Overview of Treatment OptionsPhysicians and their patients have more op-tions and more varied options for treating psoriasis than ever before, and the num-ber and variety continue to increase. The choice of therapy depends on a thorough assessment of individual patient character-istics (Figure).

Some patients with limited disease might require only topical treatment. Options in-clude corticosteroids, calcineurin inhibi-tors, immunodulators, vitamin D analogs, and retinoids. More extensive or severe

disease requires systemic therapy. Tradi-tional options for systemic therapy include methotrexate, cyclosporine, acitretin, and other types of immunomodulators.

Phototherapy, including ultraviolet B (UVB) light and psoralen with ultraviolet A light (PUVA), has a long therapeutic history in psoriasis and remains an effec-tive option. However, UVB and PUVA have become economically impractical for most patients. Insurers’ implementation of increased cost-sharing measures has shifted more of the cost to patients, many of whom must pay a share of each pho-totherapy session. A typical phototherapy regimen requires several treatment ses-sions each week for an extended period of time. Most patients with psoriasis lack the fi nancial means to assume that cost.

Increasingly, treatment of psoriasis has evolved toward use of biologic therapies, the prototype being tumor necrosis fac-tor (TNF) inhibitors. As understanding of psoriasis pathobiology has improved, new biologic agents have emerged, targeting different aspects of the infl ammatory cas-cade that drives psoriasis.

Biologic TherapyTNF InhibitorsAs a class, TNF inhibitors have proven effectiveness in psoriasis, and most have demonstrated synergy with methotrexate,

which remains an effective, low-cost, and widely used option for systemic therapy. Treatment failure or loss of disease con-trol with one agent in the class does not preclude the use of another TNF inhibitor. In general, response to second-line TNF inhibitor therapy and beyond is not as ro-bust as the initial response.

Some safety concerns have arisen re-garding TNF inhibitors, notably infection. As immunomodulators, TNF inhibitors can increase susceptibility to infection, and patients with recent or active infections should not use the agents. TNF inhibitors carry label warnings regarding the risk of infection, and the US Food and Drug Ad-ministration recently required new word-ing to include a risk of infection from Legionella spp and Listeria spp.

Use of TNF inhibitors in children and adolescents is complicated by a lack of supporting data from clinical trials. Most pediatrics-specifi c data have come from trials of etanercept.3,4 Social support has a greater role in the management of pe-diatric patients with psoriasis. Patients and families require education about the dis-ease and its management. Issues related to school, social life, and compliance pose considerations that are less prominent than with adults. Clinicians have to be vigilant about assessing a patient’s need for psy-chosocial counseling and support groups.

Psoriasis and Biologics: Current and Novel Approaches to TherapyJennifer C. Cather, MDMedical Director, Modern Dermatology and Modern Research AssociatesCo-Director, Cutaneous Lymphoma ClinicBaylor University Medical Center, Dallas, Texas

Topical agents• Corticosteroids• Calcineurin inhibitors• Immunomodulators• Vitamin D analogs• Retinoids

Biologic agentsEtanerceptInfliximabAdalimumabUstekinumab

Phototherapy• UVB• PUVA

Traditional systemic agents• Methotrexate• Cyclosporine• Acitretin• Other immunosuppressants

*Choice of therapy depends on individual patient characteristics.

Limited Disease

More Extensive/ Severe Disease

•

••

•

Figure. Many Treatment Options Exist for Psoriasis

UVB=ultraviolet B light; PUVA=psoralen with ultraviolet A light

Source: Modifi ed from Craig Leonardi, MD.

5th Annual Perspectives in Rheumatic Diseases • globalacademycme.com/rheumatology 7

Above all, a thorough evaluation of risks and benefi ts is essential when choosing therapy for young patients.

IL-12/IL-23 InhibitorsThe prototype for this therapeutic catego-ry is the monoclonal antibody ustekinum-ab, which targets the p40 fragment com-mon to interleukin (IL)-12 and IL-23. The approved indication is for adults 18 years of age or older with moderate or severe plaque psoriasis who are candi-dates for phototherapy or systemic ther-apy. Ustekinumab also has demonstrated activity in psoriatic arthritis, including response by American College of Rheu-matology criteria, improvement in the Health Assessment Questionnaire, and improvement in health-related quality of life.5,6

New Biologic CandidatesThe success of TNF inhibitors has pro-vided impetus to investigate the potential to exploit other proinfl ammatory pathways to treat psoriasis. Biologic agents in devel-opment include those that target IL-17, IL-20, IL-22, the p19 fragment of IL-23, and Janus-activated kinase (JAK).

SummaryRecognition of the debilitating effects of psoriasis has led to more aggressive treat-ment and investigation of new approaches to treat the condition. Biologic agents have demonstrated effectiveness, providing a ra-tionale to explore new proinfl ammatory pathways involved in the etiology and patho-genesis of psoriasis. Few agents have been studied extensively in children, and options for treatment are limited during pregnancy.

References 1. Johnson-Huang LM, Lowes MA, Krueger JG. Putting to-

gether the psoriasis puzzle: an update on developing tar-geted therapies. Dis Model Mech. 2012;5(4):423-33.

2. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Re-boussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41(3 pt 1):401-407.

3. Paller AS, Siegfried EC, Eichenfi eld LF, et al. Long-term etanercept in pediatric patients with plaque psoriasis. J Am Acad Dermatol. 2010;63:762-768.

4. Siegfried EC, Eichenfi eld LF, Paller AS, Pariser D, Creamer K, Kricorian G. Intermittent etanercept therapy in pediatric patients with psoriasis. J Am Acad Dermatol. 2010;63:769-774.

5. Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinum-ab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: Randomized, double-blind, placebo-controlled, crossover trial. Lancet. 2009;373:633-640.

6. Kavanaugh A, Menter A, Mendelsohn A, Shen YK, Lee S, Gottlieb AB. Effect of ustekinumab on physical func-tion and health-related quality of life in patients with pso-riatic arthritis: A randomized, placebo-controlled phase II trial. Curr Med Res Opin. 2010;26:2385-2392.

nized treatment goals, as refl ected in a vali-dated measurement. The concept of treat-ing to target has emerged more recently in the fi eld of rheumatology

Treating to target began to emerge as an accepted clinical strategy following publi-cation of the Tight Control for Rheuma-toid Arthritis (TICORA) trial.5 Patients with RA of less than 5 years’ duration were randomized to routine care or intensive treatment. Patients randomized to inten-sive treatment were evaluated monthly (as opposed to every 3 months with routine care), at which time all swollen joints were treated by direct injection.

In the intensive-treatment arm of the TICORA trial, investigators used the DAS28 to monitor response to therapy and followed an aggressive, stepped-care protocol to increase therapeutic intensity until the patient had a DAS <2.4 (defi ned as “remission”). In the routine-care arm, clinicians treated swollen joints at their own discretion, and no formal outcome was measured. Whether judged by ACR70 response or DAS <2.4, intensive treatment was associated with signifi cantly better outcomes (P<0.001).

The treating-to-target approach re-ceived further support from the European Behandel-Strategieën (BeSt) trial.6 Unlike TICORA, BeSt did not stipulate a strict therapeutic protocol. Like the TICORA trial, BeSt required clinicians to monitor response to therapy at every visit, using a combination of outcome-assessment

tools. The assessments showed signifi -cantly better results by HAQ-DI, DAS28, and radiographic joint progression in the patients randomized to outcome-directed therapeutic decisions (P=0.004).

The Treat to Target (T2T) trial em-ployed yet another strategy: outcome-di-rected therapy for RA.7 T2T demonstrated not only that treating to target led to bet-ter outcomes but also that the strategy was cost-effective, averaging about $25,000 per quality-adjusted life year (QALY), well within the widely accepted threshold of $50,000 per QALY.

Treatment OptionsMethotrexateAvailable for more than 50 years, this in-expensive antifolate remains effective for many patients with RA. When given to pa-tients with early-stage RA, methotrexate of-ten achieves results that are clinically not too dissimilar from those achieved with newer, more expensive biologic agents. Results of a large, multicenter randomized European trial demonstrated a 30% response rate (DAS28 <3.2, defi ned as low disease activ-ity) to initial treatment with methotrexate.8

At 12 months, 75% of the responding pa-tients still had low disease activity.

Another trial showed comparable initial response rates with methotrexate mono-therapy, methotrexate plus a TNF inhibi-tor, or a three-drug combination containing methotrexate.9 Likewise, a trial of a step-down therapeutic approach showed similar

disease-control rates in patients with RA who were treated continuously with metho-trexate and a TNF inhibitor or initial thera-py with the combination followed by meth-otrexate monotherapy as maintenance.10

Preferred Strategies for Integrating Biologic Therapy Into RA Treatment With so many good strategies and medica-tions available, the choice of a specifi c drug or combination of drugs for a given patient can be challenging. Generally, it is recom-mended to aggressively use methotrexate fi rst; then a combination of methotrexate and a biologic should be used, usually start-ing with a TNF inhibitor. Newer biologics are being compared to TNF inhibitors in well-controlled trials, and data about their comparative places will be forthcoming. Un-til then, one must combine an understanding of each biologic’s mechanism(s) of action with an understanding of the patient (eg, age, comorbities, other drugs) to make rational decisions even before the data are published.

SummaryClinicians have a variety of clinical assess-ment tools and a growing list of therapeu-tic options for RA. Studies have shown that outcome-directed therapy leads to better disease control and less radiographic progression. Clinicians must recognize the utility and limitations of the various means for monitoring disease control to optimize outcomes in RA. Although newer biologic agents have demonstrated effi cacy, par-

You Just Made the Diagnosis of RA: What Do You Do Now? continued from page 2

8 globalacademycme.com/rheumatology • 5th Annual Perspectives in Rheumatic Diseases

Perspectives in Rheumatic Diseases: Conference Highlights CME Post-Test Answer Sheet and Evaluation FormRelease Date of Activity: February 28, 2013 • Expiration Date of Activity for AMA PRA Credit: February 28, 2014 • Estimated Time to Complete This Activity: 1.0 hoursTo get instant CME credit online, sign in to the Web site at http://uofl .me/prd13.Upon successful completion of the online assessments, you can download and print your certifi cate of credit.1. More than ___% of patients with rheumatoid arthritis have radiographic

abnormalities within 2 years of diagnosis. A. 60% C. 80% B. 70% D. 90%

2. According to the ACR/EULAR classifi cation criteria published in 2010, a diagnosis of “defi nite RA” is indicated by a score of ___ or more out of a possible 10.

A. 2 C. 6 B. 4 D. 8

3. The concept of treating to target began to emerge as an accepted clinical strategy following publication of:

A. The ACR EULAR classifi cation criteria B. The ADACTA (ADalamumab ACTemrA) study C. The Clinical Disease Activity Index (CDAI) D. The Tight Control for Rheumatoid Arthritis (TICORA) trial

4. Which one of the following assessment tools relies entirely on patient-reported data?

A. Clinical Disease Activity Index (CDAI) B. Disease Activity Score C. Routine Assessment of Patient Index Data (RAPID)-3 D. Simplifi ed Disease Activity Index (SDAI)

5. _____ is the fi rst trial to compare two biologic agents in patients with rheumatoid arthritis who had not responded adequately to methotrexate.

A. The ADACTA study C. The MDA study B. The AMPLE study D. The TICORA trial

6. The GRAPPA approach has demonstrated that ________ is the class of drugs that has been shown to affect the status of all fi ve domains of psoriatic arthritis.

A. Anti-tumor necrosis factor agents C. Interleukins B. Biologics D. JAK inhibitors

7. In patients with psoriasis, numerous studies have found that tumor necrosis factor inhibitors have demonstrated therapeutic synergy with ________.

A. Interleukin-12/23 inhibitors B. Methotrexate C. Systemic corticosteroids D. Vitamin D analogs

8. The use of TNF inhibitors in ______ is complicated by a lack of supporting data in controlled clinical trials.

A. Elderly patients B. Patients with comorbid conditions C. Pediatric patients D. Psoriasis

ticularly in terms of slowing radiographic progression of RA, conventional therapies such as methotrexate still have an impor-tant role in the treatment of this illness.

References 1. van der Heijde DM, van Leeuwen MA, van Riel PL, van

de Putte LB. Radiographic progression on radiographs of hands and feet during the fi rst 3 years of rheumatoid arthritis measured according to Sharp’s method (van der Heijde modifi cation). J Rheumatol. 1995;22:1792-1796.

2. Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evi-dence of signifi cant radiographic damage in rheumatoid arthritis within the fi rst 2 years of disease. J Rheumatol. 1989;16:585-591.

3. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classifi cation criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569-2581.

4. Kennish LM. 2010 American College of Rheumatology/European League Against Rheumatism rheumatoid ar-thritis criteria classifi es 67% of systemic lupus erythema-tosus and 38% of psoriatic arthritis as rheumatoid ar-thritis: Implications for real world use. Poster presented at: Annual Scientifi c Meeting of the American College of Rheumatology and Association of Rheumatology Health Professionals; November 4-9, 2011; Chicago, IL. Abstract 314.

5. 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;364:263-269.

6. van der Kooij SM, le Cessie S, Goekoop-Ruiterman YP, et al. Clinical and radiological effi cacy of initial vs de-layed treatment with infl iximab plus methotrexate in patients with early rheumatoid arthritis. Ann Rheum Dis. 2009;68:1153-1158.

7. M. Vermeer, W. Kievit, I. Kuper, et al. Cost-effectiveness and cost-utility analysis for treat-to-target versus usual care in early rheumatoid arthritis: Results of the DREAM Registry. Presented at: Annual Meeting of the European League Against Rheumatism; June 6-9, 2012; Berlin, Ger-many. Abstract OP0116.

8. van Vollenhoven RF, Ernestam S, Geborek P,et al. In early RA, patients with a good initial response to MTX mono-therapy continue to have excellent clinical outcomes dur-ing the fi rst year of therapy. Poster presented at: Annual Meeting of the European League Against Rheumatism; June 11-14, 2008; Paris, France. Abstract OP0043.

9. O’Dell JR, Curtis J, Coffi eld SS, Bridges SL, Mikuls T, Moreland L. Validation of methotrexate fi rst strategy in early rheumatoid arthritis: A randomized, double-blind, 2-year trial. Presented at: Annual Scientifi c Meeting of the American College of Rheumatology and Association of Rheumatology Health Professionals; November 4-9, 2011; Chicago, IL. Abstract 1696.

10. Emery P, Smolen JS, Kavanaugh A, et al. Maintenance of biologic-free disease control in early rheumatoid arthri-tis patients after induction of low disease activity with adalimumab plus methotrexate. Ann Rheum Dis. 2011;70(suppl 3):262-263.

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