A CME-Certified Supplement to

Rheumatology News
Family Practice News
Internal Medicine News

5TH ANNUAL PERSPECTIVES

IN RHEUMATIC DISEASES
TM

CONFERENCE HIGHLIGHTS
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 activity 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 strategies 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 dierent clinical
information about patients with RA. By recognizing the similarities and dierences among these tools, clinicians can apply the
assessments that yield the most useful information about the
patient population in specific 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 benefit of patients.
LEARNING OBJECTIVES: After reading and studying this supplement, participants should be able to:
Evaluate the safety, ecacy, and applicability of available
therapies for RA in their own clinical practices
Recognize mechanistic dierences 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

he field of rheumatology has evolved

dramatically in recent years as improved understanding about the underlying mechanisms of rheumatic diseases
has driven development of new therapies
and therapeutic strategies. Clinicians can offer patients more options, many of which
were not available just a few years ago.
Increasingly, the challenge to rheumatologists and other clinicians involved in
treating rheumatic diseases is to integrate
new information and therapeutic strategies into clinical practice. This supplement
to Rheumatology News, developed from select presentations given at the 5th Annual

You Just Made the Diagnosis of RA:

What Do You Do Now?

Daniel E. Furst, MD, Conference Chair

Carl M. Pearson Professor of Medicine
Department of Medicine, Division of Rheumatology
David Geen School of Medicine at the University of California,
Los Angeles

ptimal 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 abnormalities within 2 years of diagnosis.1,2
As knowledge about the underlying
causes of RA has increased, so have the
therapeutic options. Patients benefit from
the availability of multiple treatment opJointly sponsored by:

Original Release Date: February 28, 2013

Most Recent Review Date: February 2013
Expiration Date: February 28, 2014
Estimated Time to Complete Activity: 1.0 hours
Medium or Combination of Media Used: Written Supplement
Method of Physician Participation: Journal Supplement

Perspectives in Rheumatic DiseasesTH conferencepresented by Rheumatology News,

Family Practice News and Internal Medicine
News, and held September 28 and 29, 2012,
in Newport, Californiaoffers a concise
account of recent developments in the
management of selected rheumatic diseases. The information focuses on key aspects
of patient management that are readily applicable to clinical practice.
The information reflects current knowledge, standards, and practices in rheumatic
diseases. We hope that readers will find the
summaries informative and readily applicable to clinical practice.

tions, but the expanding armamentarium

also complicates therapeutic decision making. The success of therapeutic strategies
depends on a clinicians ability to integrate
information from multiple sources, to recognize the value and the limitations of that
information, and to apply the information
to optimize patient outcomes.

Accurate Clinical Assessment

The 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 laboratoThis activity is supported by
educational grants from:

and

To get instant CME credit online, go to http://uofl.me/prd13

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
scientific 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 serviceswith the exemption of nonprofit or government
organizations and nonhealth-related companieswith
which they or their spouse/partner have, or have had, a
relevant financial relationship within the past 12 months.
For this purpose, we consider the relevant financial relationships of a spouse/partner of which they are aware to be
their financial relationships.
2. Describe what they or their spouse/partner received (eg,
salary, honorarium).
3. Describe their role.
3. No relevant financial relationships.
Jennifer C. Cather, MD, has been a consultant and/or investigator and/or speaker for Abbott, Amgen, Celgene, Janssen
Biotech, Novartis, and Pfizer.
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, Pfizer, Roche, and UCB.
Joel M. Kremer, MD, has been a consultant and/or speaker
for Abbott, Amgen, Bristol-Myers Squibb, Genentech, and Pfizer.
Christopher T. Ritchlin, MD, MPH, has been an investigator and/or consultant for Amgen, Janssen Biotech , Pfizer,
and UCB.
Sylvia Reitman, MBA, has no relevant financial relationships with any commercial interests.
Charles Bankhead has no relevant financial relationships
with any commercial interests.
TO OBTAIN CME CREDIT: To get instant CME credits
online, go to http://uofl.me/prd13. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate
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 openthis 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 certificate. Please note, certificates will not
be mailed, so be sure to print a copy for your records. If you
have any questions or diculties, please contact the University
of Louisville School of Medicine Continuing Medical Education
oce at cmepd@louisville.edu

REGISTER NOW

6th Annual Perspectives in

Rheumatic DiseasesTM
a continuing medical education conference
September 20-21, 2013
Mandalay Bay Hotel, Las Vegas
Jointly sponsored by

globalacademycme.com/rheumatology

ry findings developed to guide clinicians in

the differential diagnosis and classification
of new patients and to make that diagnosis
earlier in the disease course. The guidelines
have reasonable sensitivity for RA but lack
specificity.
Investigators in a recent study evaluated
the specificity of the ACR/EULAR criteria in 112 patients with established rheumatologic 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 erythematosus, 50% of those with osteoarthritis,
and 37.5% of those with psoriatic arthritis.

Assessment Tools
To guide decision making, clinicians can
rely on a variety of clinical parameters and
assessments, including joint counts, patient and physician global assessments, the
Health Assessment Questionnaire (HAQ),
laboratory values, and categorical outcome
measures, such as ACR response. In recent years, multiple continuous assessment
tools have been developed and refined,
such as the Disease Activity Score (DAS),
the Simplified 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 decisions lead to better outcomes in RA. Appreciating the strengths and limitations of
currently available assessment tools can
help clinicians use those tools to maximize
the benefit for patients.
The 28-joint DAS (DAS28) and the
44-joint version of the instrument have
been validated as a reflection 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 five measures: tender and swollen joint count, Patients Global
Assessment (PGA), Physicians Global Assessment, and C-reactive protein (CRP) or
erythrocyte sedimentation rate levels.
The SDAI has good correlation with
the Health Assessment Questionnaire Disability Index (HAQ-DI), DAS28, and ACR
response. The CDAI simplifies office assessment by eliminating the laboratory
(CRP) component of the SDAI. This index correlates well (~90%) with the SDAI
and DAS28.5
The Routine Assessment of Patient Index Data (RAPID)-3 combines three types
2

Figure. 2010 ACR/EULAR RA

Classification Criteria
1 joint with synovitis (excluding the DIP,
first MTP, and first 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
1 large joint
2-10 large joints
1-3 small joints
4-10 small joints
>10 joints (1 small joint)

(0-5)
0
1
2
3
5

Serology
Negative RF and ACPA
Low-positive RF or ACPA
High-positive RF or ACPA

(0-3)
0
2
3

Symptom Duration
<6 weeks
6 weeks

(0-1)
0
1

Acute-Phase Reactants
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR

(0-1)
0
1

Patients with a score of 6 have definite 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

of information: Modified HAQ-DI (an

8-question version of the HAQ-DI), patient-reported pain, and the PGA. The instrument relies entirely on patient-reported 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 clinician time commitment. However, the instrument has relatively poor correlation
with the DAS28 and the CDAI (only ~73%
for either), both of which provide important information about disease status.6

Treating to Target
Clinical targets have been widely used in
disease management: hypertension, dyslipidemia, and diabetes, to name a few. For
each condition, clinicians have well-recogcontinued on page 7

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

At the Cutting Edge: Newest Data on RA Therapy

Joel M. Kremer, MD
Pfa Family Professor of Medicine,
Albany Medical College
Director of Research, The Center for Rheumatology
Albany, NY

irect comparisons of therapies

provide valuable clinical information, but remain all too uncommon in some fields of medicine. The
field of rheumatology has benefited from
recent expansion of therapeutic options
for rheumatoid arthritis (RA), but, until
recently, no clinical trials had directly compared newer agents against one another. At
the 2012 meeting of the European League
Against Rheumatism (EULAR), two presentations attracted considerable attention because they represented the rarest
of clinical trials: randomized comparisons
of different biologic therapies for RA. The
results have potential to influence clinical
practice regarding management of patients
with RA.

Anti-interleukin 6 vs TNF Inhibitor

The 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 field of RA, the antiinterleukin (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 erythrocyte 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 administered 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 assessed 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 significantly
between the treatment groups.

Primary Outcomes
The primary analysis demonstrated a

Table. ADACTA Primary Endpoint: Change in DAS28 From Baseline to

Week 24 (ITT Population)*
n
Adjusted mean
Dierence
95% CI for dierence
P value

ADA 40 mg SC+ IV Placebo

TCZ 8 mg/kg IV+ SC Placebo

162
-1.8

163
-3.3

-1.5
-1.8 to -1.1
<0.0001

*Analysis of variance (model included baseline value plus the stratification 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 Patients 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=confidence interval; LOCF=last observation carried forward;
TJC=tender joint count; SJC=swollen joint count; ESR=erythrocyte sedimentation rate; VAS=visual analog scale
Source: Gabay C et al.1

3.3-point decline in mean DAS28 score in

the tocilizumab arm compared with 1.8 in
the adalimumab group, a statistically significant difference in favor of the IL-6 inhibitor (P<0.0001) (Figure). A difference in
DAS28 favoring tocilizumab emerged after 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 included DAS28 remission (<2.6) or low disease 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 definition for remission. That compared
with a remission rate of 10.5% and low disease activity in 19.8% of patients randomized to adalimumab (P<0.0001 vs tocilizumab for both outcomes).
Investigators also assessed the proportion of patients in each group who met
American College of Rheumatology (ACR)
response criteria. The results showed a significant 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 favored tocilizumab treatment (30.7% vs

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

29.0%), resulting in a significant advantage

for CDAI remission/low disease activity
combined (P=0.0003).

Safety
Analysis 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 tocilizumab versus adalimumab, and the results confirmed the superiority hypothesis.
The safety profile was similar in the two
groups, and no new or unexpected adverse
events occurred in either group.

Add-On Biologic Therapy

In contrast to the ADACTA trial, the
Abatacept Versus Adalimumab Comparison in Biologic-Nave Rheumatoid Arthritis Subjects With Background Methotrexate (AMPLE) study involved patients with
RA currently treated with methotrexate.2
The trial was the first to compare two
biologic agents in patients whose RA had
not responded adequately to methotrexate. The trial was statistically powered to
demonstrate noninferiority of abatacept
(a fusion-protein construct that inhibits
continued on page 5
3

Psoriatic Arthritis: Maximizing Patient Outcomes

Christopher Ritchlin, MD, MPH
Professor of Medicine
Director, Translational Immunology Research Center
University of Rochester Medical Center
Rochester, NY

matologists and dermatologists, as well as

patients primary care physicians.

Figure 2. Criteria for Minimal

Disease Activity (MDA)

Evaluation of the Patient With PsA

Conventional 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 significant disease
burden in patients with PsA because the
disease is distal interphalangeal predominant or has substantial involvement of
the feet. Characterizing the true extent of
disease burden in PsA may require assessment of 66/68-joint activity, which is time
consuming but provides a more accurate
clinical picture of the patient.
Enthesitis is a common finding in PsA
and might involve multiple sites, including
the supraspinatus, lateral epicondyle, iliac
crest, trochanter, patellar/quadriceps, and
plantar fascia/Achilles tendon. The evaluation requires relatively little time and usually is quite informative about
the extent of tenderness and
Figure 1. The Psoriatic March
inflammation.
In contrast to the traditional
Insulin
Psoriasis
goal
of remission in RA, the
resistance
treatment goal in PsA focuses
Systemic
inflammation
on attainment of minimal disease activity (MDA). MDA criObesity
Endothelial
teria encompass a clinical specdysfunction
Myocardial
trum that includes tender and
infarction
swollen joints, extent of body
Smoking/alcohol
surface area involvement or exAtherosclerosis
tent of clearance, pain, global
= association
activity, disability, and tender
Source: Adapted from Boehncke WH et al.
points (Figure 2).3

Patients are classified 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 1

mproved understanding of psoriatic

arthritis (PsA) has led to the recognition that the condition confers adverse 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 patients with PsA also develop psoriasis and
related psoriatic comorbidities: nail disease, obesity, hypertension, type 2 diabetes,
hyperlipidemia, steatosis, metabolic syndrome, myocardial infarction, and anxiety/
depression. Between 10% and 15% of patients develop inflammatory bowel disease.
The constellation of comorbidities and
disease manifestations has been characterized as the psoriatic march, which begins

with obesity, psoriasis, smoking, and/or

alcohol consumption (Figure 1).2 Those
factors induce and maintain systemic inflammation, 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 musculoskeletal and skin manifestations, risk factors
for diabetes and cardiovascular disease,
and the psychoemotional effects of the
condition. A comprehensive approach requires close collaboration between rheu4

Assessing Therapies and Response

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis
(GRAPPA) has developed evidence-based
guidance for use of therapeutic interventions in PsA.4 The approach encompasses
the five domains that require consideration
in the development of an effective treatment 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, specifically

PASI=Psoriasis Area and Severity Index;

BSA=body surface area; VAS=visual
analog scale; HAQ=Health Assessment
Questionnaire
Source: Coates L et al.3

tumor necrosis factor (TNF) inhibitors,

have been shown to affect the status of all
five 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 antibodies, all of which are used to assess disease
activity in RA. Instead, clinicians often base
therapeutic choices on the sum of considerations that can influence the choice: efficacy in joints and skin, risk of progression,
quality-of-life issues, safety, mode of administration, and economic realities.
Clinicians do have some evidence to help
them identify patients who are likely to progress 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 inflammation,
sex (women at higher risk), and clinical subgroup (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 patients who achieved MDA had a significantly lower prevalence of obesity and
that weight loss improved a patients odds
of achieving MDA during treatment with
TNF inhibitors.8,9

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

Therapeutic Options
Methotrexate, 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 considerable number of patients dropped out
before the end of the study. However,
the results showed no significant effect
of methotrexate on the primary endpoint
(Psoriatic Arthritis Response Criteria) or
key secondary outcomes (American College of Rheumatology [ACR] response,
DAS28, swollen/tender joint counts, and
proinflammatory markers).
In contrast to methotrexate, TNF inhibitors 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 Psoriasis Area and Severity Index score improvements 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 flare and/or optimizing use of nonsteroidal anti-inflammatory 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).

Summary
PsA and RA have some clinical features in
common but also differ in many respects,
including clinical manifestations, therapeutic options, and response to therapy.
Patients with PsA require a comprehensive
approach to clinical management, beginning with early diagnosis and treatment.
Rheumatologists, dermatologists, and primary 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 fit into the current
DMARD armamentarium? J Rheumatol. 2001;28(suppl
62):27-35.
2. Boehncke WH, Boehncke S, Schn MP. Managing
comorbid disease in patients with psoriasis. BMJ.
2010;340:b5666.
3. Coates L, Fransen J, Helliwell PS. Defining minimal disease 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 indicators 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 outpatient 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 prospective 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- 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 randomized placebo-controlled trial of methotrexate in psoriatic
arthritis. Rheumatology (Oxford). 2012;51:1368-1377.
11. Mease PJ. Psoriatic arthritis: Update on pathophysiology, 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 spondylarthritis 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

signaling associated with T-cell activation)
versus adalimumab.
Investigators in the United States, the
Netherlands, and Argentina randomized
646 patients with active RA despite methotrexate therapy to subcutaneous abatacept
125 mg weekly or to subcutaneous adalimumab 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 characteristics did not differ notably between
treatment groups. The patients had a median RA duration of almost 2 years, reflecting a longer treatment history than that of
the ADACTA study population.
The results showed that 64.8% of patients 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 significant,
but fell without the statistical limits for noninferiority, 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 remission 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 significantly between the groups, and both drugs demonstrated comparable inhibition of radiographic progression.
Similarity between the two groups continued with the safety data, which showed
no differences in adverse events, serious adverse events, or infections. Discontinuation
due to adverse events occurred slightly less
often with abatacept, as did injection-site reactions. One sudden cardiac death occurred
in the abatacept arm and involved a 66-yearold man with a history of hypertension.

Summary
Two recent clinical trials have provided

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

continued from page 3

much-needed data regarding head-tohead comparisons of biologic agents for
RA. One trial demonstrated superiority
of tocilizumab versus adalimumab for reducing the DAS28 score, including remission and low disease activity. The other
trial showed that abatacept and adalimumab had similar efficacy, as defined by
the proportion of patients who attained
ACR20 responses during a year of treatment and follow-up. Results of these trials offer clinical guidance to clinicians
who treat patients with RA.

References
1. 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 Rheumatism annual; June 6-9, 2012; Berlin, Germany. Abstract
OP0022.

Psoriasis and Biologics: Current and Novel

Approaches to Therapy
Jennifer C. Cather, MD
Medical Director, Modern Dermatology and Modern Research Associates
Co-Director, Cutaneous Lymphoma Clinic
Baylor University Medical Center, Dallas, Texas

he conceptual framework underlying the etiology of psoriasis has

undergone dramatic transformation in recent years. Recognition of the
immunologic and inflammatory processes
that drive the condition has led to the
development of therapies that more specifically 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 appreciation of the diversity of adverse effects
associated with the condition: arthritis,
liver disease, diabetes and metabolic syndrome, obesity, cardiovascular disease,
depression, and inflammatory bowel disease. Moreover, psoriasis exacts a heavy
quality-of-life toll, disrupting sleep, ambulation, manual dexterity, and the ability 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 associated with disability, including congestive
heart failure, chronic lung disease, diabetes, arthritis, and myocardial infarction,
among others.2 The economic impact of
psoriasis cannot be overlooked. For many
patients, psoriasis leads to substantial absenteeism from work and reduced productivity at work.
By targeting the underlying biologic processes of psoriasis, modern therapies afford greater opportunity to minimize the
cosmetic, systemic, emotional, social, and
economic effects of the condition.

Overview of Treatment Options

Physicians and their patients have more options and more varied options for treating
psoriasis than ever before, and the number and variety continue to increase. The
choice of therapy depends on a thorough
assessment of individual patient characteristics (Figure).
Some patients with limited disease might
require only topical treatment. Options include corticosteroids, calcineurin inhibitors, immunodulators, vitamin D analogs,
and retinoids. More extensive or severe
6

Figure. Many Treatment Options Exist for Psoriasis

Traditional systemic agents

Methotrexate
Cyclosporine
Acitretin
Other immunosuppressants

Topical agents

Corticosteroids
Calcineurin inhibitors
Immunomodulators
Vitamin D analogs
Retinoids

Phototherapy
UVB
PUVA

Limited Disease

Biologic agents
Etanercept
Infliximab
Adalimumab
Ustekinumab

*Choice of therapy depends on individual

patient characteristics.

More Extensive/ Severe Disease

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

Source: Modified from Craig Leonardi, MD.

disease requires systemic therapy. Traditional 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 effective 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 phototherapy session. A typical phototherapy
regimen requires several treatment sessions each week for an extended period of
time. Most patients with psoriasis lack the
financial means to assume that cost.
Increasingly, treatment of psoriasis has
evolved toward use of biologic therapies,
the prototype being tumor necrosis factor (TNF) inhibitors. As understanding of
psoriasis pathobiology has improved, new
biologic agents have emerged, targeting
different aspects of the inflammatory cascade that drives psoriasis.

Biologic Therapy
TNF Inhibitors
As 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 control 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 robust as the initial response.
Some safety concerns have arisen regarding 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 Administration recently required new wording 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-specific data have come from
trials of etanercept.3,4 Social support has
a greater role in the management of pediatric patients with psoriasis. Patients and
families require education about the disease 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 patients need for psychosocial counseling and support groups.

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

Above all, a thorough evaluation of risks

and benefits is essential when choosing
therapy for young patients.

IL-12/IL-23 Inhibitors
The prototype for this therapeutic category is the monoclonal antibody ustekinumab, which targets the p40 fragment common 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 candidates for phototherapy or systemic therapy. Ustekinumab also has demonstrated
activity in psoriatic arthritis, including
response by American College of Rheumatology criteria, improvement in the
Health Assessment Questionnaire, and
improvement in health-related quality of
life.5,6

New Biologic Candidates

The success of TNF inhibitors has provided impetus to investigate the potential
to exploit other proinflammatory pathways
to treat psoriasis. Biologic agents in development include those that target IL-17, IL20, IL-22, the p19 fragment of IL-23, and
Janus-activated kinase (JAK).

Summary
Recognition of the debilitating effects of
psoriasis has led to more aggressive treatment and investigation of new approaches
to treat the condition. Biologic agents have
demonstrated effectiveness, providing a rationale to explore new proinflammatory
pathways involved in the etiology and pathogenesis 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 together the psoriasis puzzle: an update on developing targeted therapies. Dis Model Mech. 2012;5(4):423-33.
2. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin 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, Eichenfield LF, et al. Long-term
etanercept in pediatric patients with plaque psoriasis. J
Am Acad Dermatol. 2010;63:762-768.
4. Siegfried EC, Eichenfield 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. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for
psoriatic arthritis: Randomized, double-blind, placebocontrolled, 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 function and health-related quality of life in patients with psoriatic arthritis: A randomized, placebo-controlled phase
II trial. Curr Med Res Opin. 2010;26:2385-2392.

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

nized treatment goals, as reflected in a validated measurement. The concept of treating to target has emerged more recently in
the field of rheumatology
Treating to target began to emerge as an
accepted clinical strategy following publication of the Tight Control for Rheumatoid Arthritis (TICORA) trial.5 Patients
with RA of less than 5 years duration were
randomized to routine care or intensive
treatment. Patients randomized to intensive 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 (defined
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 significantly better
outcomes (P<0.001).
The treating-to-target approach received further support from the European
Behandel-Strategien (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 significantly 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 employed yet another strategy: outcome-directed therapy for RA.7 T2T demonstrated
not only that treating to target led to better 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 Options
Methotrexate
Available for more than 50 years, this inexpensive antifolate remains effective for
many patients with RA. When given to patients with early-stage RA, methotrexate often 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, defined as low disease activity) to initial treatment with methotrexate.8
At 12 months, 75% of the responding patients still had low disease activity.
Another trial showed comparable initial
response rates with methotrexate monotherapy, methotrexate plus a TNF inhibitor, or a three-drug combination containing
methotrexate.9 Likewise, a trial of a stepdown therapeutic approach showed similar

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

continued from page 2

disease-control rates in patients with RA

who were treated continuously with methotrexate and a TNF inhibitor or initial therapy with the combination followed by methotrexate monotherapy as maintenance.10

Preferred Strategies for Integrating

Biologic Therapy Into RA Treatment
With so many good strategies and medications available, the choice of a specific drug
or combination of drugs for a given patient
can be challenging. Generally, it is recommended to aggressively use methotrexate
first; then a combination of methotrexate
and a biologic should be used, usually starting 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. Until then, one must combine an understanding
of each biologics 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.
Summary
Clinicians have a variety of clinical assessment tools and a growing list of therapeutic 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 efficacy, par7

ticularly in terms of slowing radiographic

progression of RA, conventional therapies
such as methotrexate still have an important 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 first 3 years of rheumatoid
arthritis measured according to Sharps method (van der
Heijde modification). J Rheumatol. 1995;22:1792-1796.
2. Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid
arthritis within the first 2 years of disease. J Rheumatol.
1989;16:585-591.
3. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid
arthritis classification criteria: An American College of
Rheumatology/European League Against Rheumatism
collaborative initiative. Arthritis Rheum. 2010;62:25692581.

4. Kennish LM. 2010 American College of Rheumatology/

European League Against Rheumatism rheumatoid arthritis criteria classifies 67% of systemic lupus erythematosus and 38% of psoriatic arthritis as rheumatoid arthritis: Implications for real world use. Poster presented
at: Annual Scientific 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 efficacy of initial vs delayed treatment with infliximab 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, Germany. Abstract OP0116.

8. van Vollenhoven RF, Ernestam S, Geborek P,et al. In early

RA, patients with a good initial response to MTX monotherapy continue to have excellent clinical outcomes during the first year of therapy. Poster presented at: Annual
Meeting of the European League Against Rheumatism;
June 11-14, 2008; Paris, France. Abstract OP0043.
9. ODell JR, Curtis J, Coffield SS, Bridges SL, Mikuls T,
Moreland L. Validation of methotrexate first strategy in
early rheumatoid arthritis: A randomized, double-blind,
2-year trial. Presented at: Annual Scientific 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 arthritis patients after induction of low disease activity with
adalimumab plus methotrexate. Ann Rheum Dis. 2011;70
(suppl 3):262-263.

To get instant CME credit online, go to http://uofl.me/prd13

Perspectives in Rheumatic Diseases: Conference Highlights CME Post-Test Answer Sheet and Evaluation Form
Release 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 hours

To 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 certificate 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%

5. _____ is the first 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

2. According to the ACR/EULAR classification criteria published in 2010, a

diagnosis of definite RA is indicated by a score of ___ or more out of a
possible 10.
A. 2
C. 6
B. 4
D. 8

6. The GRAPPA approach has demonstrated that ________ is the class of

drugs that has been shown to affect the status of all five domains of
psoriatic arthritis.
A. Anti-tumor necrosis factor agents
C. Interleukins
B. Biologics
D. JAK inhibitors

3. The concept of treating to target began to emerge as an accepted clinical

strategy following publication of:
A. The ACR EULAR classification criteria
B. The ADACTA (ADalamumab ACTemrA) study
C. The Clinical Disease Activity Index (CDAI)
D. The Tight Control for Rheumatoid Arthritis (TICORA) trial

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

4. Which one of the following assessment tools relies entirely on patientreported data?
A. Clinical Disease Activity Index (CDAI)
B. Disease Activity Score
C. Routine Assessment of Patient Index Data (RAPID)-3
D. Simplified Disease Activity Index (SDAI)

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

REGISTER NOW AT WWW.GLOBALACADEMYCME.COM/RHEUMATOLOGY

6TH ANNUAL PERSPECTIVES IN RHEUMATIC DISEASES

TM

A CONTINUING MEDICAL EDUCATION CONFERENCE

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

CHAIR
Daniel E. Furst, MD

CO-CHAIRS
Brian Mandell, MD, PhD

Carl M. Pearson Professor of Medicine

David Geen School of Medicine
University of California, Los Angeles (UCLA)

Professor and Chairman of Medicine

The Cleveland Clinic, Ohio

Jointly sponsored by

University of Glasgow
Scotland, UK

Professor Iain McInnes, MRCP, PhD

Introducing: Fellows Day

September 19, 2013
EARN UP TO 16 CME CREDITS

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