Rheumatoid Arthritis in Practice
An Expert Commentary With
Roy Fleischmann, MD
A Clinical Context Report
Rheumatoid Arthritis in Practice
Jointly Sponsored by:
and
Rheumatoid Arthritis in Practice
Expert Commentary
Supported in part by educational grants
from Abbott and Centocor Ortho Biotech.
Rheumatoid Arthritis in Practice
Clinical Context Series
The goal of this series is to provide up-todate information and multiple perspectives
on the pathogenesis, symptoms, risk
factors, and complications of rheumatoid
arthritis as well as current and emerging
treatments and best practices in the
management of rheumatoid arthritis.
Rheumatoid Arthritis in Practice
Clinical Context Series
Target Audience
Rheumatologists, pain management
specialists, geriatricians, family
practice/primary care physicians, nurses,
nurse practitioners, physician assistants,
pharmacists. and other healthcare
professionals involved in the management
of patients with rheumatoid arthritis.
Activity Learning Objective
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Discussant
Roy Fleischmann, MD
Clinical Professor of Medicine
University of Texas Southwestern
Medical Center
Dallas, Texas
Disclosure Information
Roy Fleischmann, MD,
has disclosed that he has no relevant financial
relationships or conflicts of interest to report.
Disclosure Information
Dori F. Zaleznik, MD, Associate Clinical Professor of
Medicine, Harvard Medical School, Boston; Nancy Walsh;
and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse
Planner; have disclosed that they have no relevant financial
relationships or conflicts of interest with commercial interests
related directly or indirectly to this educational activity.
The staff of The University of Pennsylvania School of
Medicine Office of CME, MedPage Today, and Projects In
Knowledge have no relevant financial relationships or
conflicts of interest with commercial interests related directly
or indirectly to this educational activity.
Rheumatoid Arthritis: Scope of the Problem
• 1,293,000 Americans ages 18 and older have
rheumatoid arthritis
• Across most developed countries the
incidence is similar, at approximately 0.5% to
1% of adults
Reference: Helmick C, et al “Estimates of the prevalence of arthritis and other
rheumatic conditions in the United States” Arthritis Rheum 2008; 58: 15-25.
The Methotrexate Era
• Before the mid 1980s treatment of active
RA consisted primarily of gold or penicillamine
• RA is frequently severe and debilitating; the side
effects of DMARDs were problematic
• In 1988 methotrexate was approved for use in RA
which was a quantum leap forward
• Methotrexate remains the cornerstone of therapy
of RA today
The Tumor Necrosis Factor (TNF) Era
• The first biologic for RA, etanercept (Enbrel), was
approved in the U.S. in 1998
• There are now five TNF inhibitors on the market
• The TNF inhibitors were a significant addition to
our armamentarium which has led to dramatic
improvements in patient outcomes
Definitions of Remission in RA
• The Disease Activity Score [28 joints] (DAS28) is a
disease measure which utilizes the number of tender
and swollen joints in a 28 joint count, the erythrocyte
sedimentation rate or the C-reactive protein (CRP),
and the patient general health on a visual analog scale
(0-100). DAS28 (ESR) remission is a score below 2.6
Definitions of Remission in RA (cont’d)
• The Simplified Disease Activity Index (SDAI) is a
disease measure which adds the tender and
swollen joints (28 count), CRP, patient’s global
disease activity, and physician’s global assessment.
SDAI remission is a score <3.3
• The Clinical Disease Activity Index (CDAI) is
similar to the SDAI except no laboratory test
measurements are included. Remission is a score
below 2.8
Definitions of Remission in RA (cont’d)
• Recently, the American College of Rheumatology
and the European League Against Rheumatism
developed provisional remission criteria for use in
clinical trials. These criteria include either a score
of ≤3.3 on the SDAI or scores no higher than 1 on
tender joint count, swollen joint count, patient
global assessment, and CRP in mg/dL
Reference: Felson D, et al “American College of Rheumatology/European League
Against Rheumatism provisional definition of remission in rheumatoid arthritis for
clinical trials” Arthritis Rheum 2011; 63: 573-586.
Initiating Treatment
• Start with methotrexate, unless contraindicated
• Combine with folic acid (at least 1 mg per day)
• Consider using low-dose corticosteroids, if
necessary
• Reassess patient in eight weeks by measuring
DAS28, CDAI, SDAI and/or RAPID3
Initiating Treatment (cont’d)
• If patient responds (such as with a decrease in
DAS28 of 1.2 or more) continue on methotrexate
for an additional eight weeks
• With further response, continue methotrexate and
taper steroids
Approved Biologic Agents
• Etanercept (Enbrel) is a fusion protein given as a
weekly, 50-mg subcutaneous injection in RA
• Infliximab (Remicade) is a chimeric monoclonal
antibody given in doses of 3 mg/kg to 10 mg/kg
every four to eight weeks
• Adalimumab (Humira) is a fully human
monoclonal antibody given as a subcutaneous
injection of 40 mg every other week and
occasionally weekly
Approved Biologic Agents (cont’d)
• Certolizumab pegol (Cimzia) is a pegylated Fab’
fragment of a humanized monoclonal antibody,
given in subcutaneous doses of 200 mg every
other week or 400 mg a month after a loading dose
• Golimumab (Simponi) is another human
monoclonal antibody given subcutaneously in
doses of 50 mg once a month
Continuing Treatment
• If response is inadequate, consider adding a
TNF inhibitor
• Assess response at 12 weeks; if sufficient,
continue anti-TNF treatment until disease
activity is low
• If the response is not adequate after 12
weeks, consider switching to another TNF
inhibitor or a different class of biologic
Biologic Drugs for RA-2
• Several other types of biologic drugs (e.g., a
T-cell costimulation modulator and
monoclonal antibodies against IL-6 and CD20)
also have been developed, and are typically
given to patients who do not fully respond to a
TNF inhibitor. As with the TNT inhibitors, they
generally are given in combination with
methotrexate
Biologic Drugs for RA-2 (cont’d)
• Abatacept (Orencia) is a selective costimulation
modulator of T cells given as a monthly
intravenous infusion in doses ranging from 500
to 1,000 mg depending on patient body weight,
after a loading dose
• Tocilizumab (Actemra) is a humanized
monoclonal antibody that binds to the interleukin
(IL)-6 receptor. It is given by intravenous infusion
every four weeks in doses of 4 to 8 mg/kg
Biologic Drugs for RA-2 (cont’d)
• Rituximab (Rituxan) is a chimeric monoclonal
antibody against the CD20 protein on the surface
of B cells. This drug is given as two 1,000 mg
infusions; the frequency of repeat therapy is not
clear but certainly not before 16 weeks after the
last infusion
Common Adverse Effects of the Biologic
Drugs
• Etanercept: Infections and injection site
reactions
• Infliximab: Upper respiratory tract infections,
sinusitis, pharyngitis, infusion reactions,
headache, and abdominal pain
• Adalimumab: Upper respiratory tract
infections, sinusitis, injection site reactions,
headache, and rash
Common Adverse Effects of the Biologic
Drugs (cont’d)
• Certolizumab pegol: Upper respiratory tract
infections, rash, and urinary tract infections
• Golimumab: Upper respiratory tract infections,
nasopharyngitis
• Abatacept: Headache, upper respiratory tract
infections, nasopharyngitis, and nausea
Common Adverse Effects of the Biologic
Drugs (cont’d)
• Tocilizumab: Upper respiratory tract infections,
nasopharyngitis, headache, hypertension,
increased alanine transaminase levels
• Rituximab: Upper respiratory tract infection,
nasopharyngitis, urinary tract infection, bronchitis.
Other potentially important events include infusion
reactions, serious infections, cardiovascular
events and, progressive multifocal
leukoencephalopathy
The Patient’s Choice
• Explain the similarities and differences of the
drugs
• Mode of administration and timing differ among
the biologics
• Efficacy and side effects are generally similar
• Encourage the patient to choose a treatment
based on personal preference unless their
insurance plan specifies which therapies are
permitted
Serious Infections
• Most viral infections are not a concern
• Bacterial infections

Treat until resolved

Withhold biologic therapy until resolved

Reconsider biologic therapy if infections recur
• Screen for tuberculosis and watch for
opportunistic infections
Other Safety Issues
• Avoid TNF inhibitors in patients with congestive
heart failure NYHA Class III/IV or demyelinating
disease
• Lymphomas and other malignancies have been
reported in patients on biologics but don’t appear
to be a major clinical concern
• Patients should take precautions against skin
cancer
New Drugs in the Pipeline
• Additional IL-6 antibodies
• Other anti-CD20 antibodies
• Kinase inhibitors

JAK inhibitors

SYK inhibitors
Phase III Study of Ofatumumab
Responses at week 24
• Results of a phase III trial of the monoclonal antibody ofatumumab, which
targets a different CD20 epitope than rituximab, were presented as an
abstract at the 2011 EULAR meeting
• A total of 260 patients with active RA who had not previously been treated
with biologic drugs were enrolled and randomized to receive two infusions
(each 700 mg) or placebo along with methotrexate
(P<0.001)
Source: Taylor P, et al “Ofatumumab, a fully human anti-CD20 MAB in the treatment
of biologic-naïve rheumatoid arthritis patients: a randomized, double-blind, placebocontrolled clinical trial” EULAR 2011; Abstract OP0019.
Monotherapy With an Oral JAK Inhibitor
• A phase 3 study of monotherapy with the oral JAK inhibitor
tofacitinib randomized 610 patients with active RA to 5 or 10 mg of
tofacitinib twice daily or placebo
• After three months of treatment, significantly more patients on the
active treatment had ACR20 responses (P<0.0001)
Source: Fleischmann R, et al “Phase 3 study of oral JAK inhibitor tasocitinib (CP690,550) monotherapy in patients with active rheumatoid arthritis”; ACR 2011;
Abstract L8.
Summary
At the end of this activity, participants should understand:

An estimated 1.3 million American adults have RA

Dramatic changes have occurred in the treatment
and outcome of patients with the development of
new therapies, beginning with the TNF inhibitors in
the late 1990s

The goal of treatment today is remission, which has
been defined in several ways, including the DAS28
score, SDAI, CDAI, and a provisional ACR/EULAR
definition
Summary

Most patients begin treatment with methotrexate,
which results in remission at 16 weeks in about
one-third of patients

If patients continue to have disease activity, the
usual next step is to treat with a TNF inhibitor

There are currently five TNF inhibitors on the
market, which vary in mode and frequency of
administration. The drugs are generally similar in
efficacy and side effect profiles
Summary

A safety concern with the biologic drugs is the
potential for serious infections, so monitoring is
needed

Other options also are now available for patients
who don’t respond to TNF inhibitors or who
experience adverse events. The choice of which
drug to use may reflect the decision of the patient’s
insurance company or the patient’s preference

A number of new drugs are in the pipeline such as
JAK and SYK inhibitors, and studies now under way
should help clarify their therapeutic niches