F E AT U R E | PHARMACOLOGIC APPROACHES TO RHEUMATOID ARTHRITIS
Pharmacologic Approaches to
By JOAN M. BATHON, MD
This discussion is based on a presentation from RA is a systemic disease, so patients often present with
the American Academy of Pain Management’s 21st constitutional symptoms, such as fever and weight loss.
Annual Clinical Meeting, September 21-24, 2010, in Cachexia caused by tumor necrosis factor (TNF) and
Las Vegas, Nevada. other cytokines can cause muscle atrophy and osteopenia,
not just in the hands, but in the legs and arms as well.
heumatoid arthritis (RA) is a chronic Extra-articular involvement is typified serologically by
R inflammatory disease that causes significant
disability and reduces lifespan. Early aggressive
treatment to achieve remission is the goal of
therapy. This discussion will provide a bird’s eye view of
RA, including the clinical aspects, pharmacologic agents,
inflammatory signals, including elevated erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP),
decreased albumin, polyclonal gammopathy, and anemia,
most of which are related to increased interleukin 6 (IL-6).
Patients with RA also have higher rates of overall
and strategies for treatment, as therapies for RA have mortality, cardiovascular-associated mortality and
increased exponentially in the last 10 years. morbidity, and cardiovascular risk factors. This disease
limits life span by about 5 to 8 years, and the major cause
Disease Overview of excess deaths is cardiovascular disease (3).
RA affects 1 in every 100 people in the United States (1),
women more than men and starts in the middle years of Treatment Strategies
life. Inflammation is the primary driver of this disease, Treating RA is not necessarily about which pharmacologic
and the cardinal signs of inflammation are the focus of agents are used, but rather about the treatment approach.
treatment in RA. Chronic inflammation destroys the Treatment of RA should be early and aggressive. Use a
joints by eroding bone, by destroying and rupturing combination of agents where appropriate and have a
tendons and ligaments, and by eroding cartilage. The targeted goal. Reducing pain, stiffness, and fatigue is our
synovium becomes hypertrophied with cellular main goal for improving quality of life in RA patients.
infiltration—T cells, B cells, and some macrophages. As
the disease progresses and becomes more aggressive,
intense synovial hypertrophy occurs that in some ways Figure 1. Classification Criteria for Rheumatoid
acts like a malignancy by growing into tissue. The Arthritis
synovium secretes many of the same substances that
Four of the following 7 factors are present:
cancer cells do, such as proteases that degrade cartilage
• Morning stiffness ≥1 hour
and bone, but they are not mitotic figures. This is not a
• Simultaneous arthritis of ≥3 joints
proliferative process, but a hypertrophic process.
• Arthritis of hand joints
The classification criteria for RA include 4 of the 7
• Symmetrical arthritis
criteria in Figure 1 (2). The primary areas of involvement
• Rheumatoid nodules
are in the hands, and polyarthritis of 3 or more joints is
• Serum rheumatoid factor
typically present. Genetic predisposition, autoimmune
• Typical radiographic changes in hands and wrists
components, and the patient’s environment are other
factors to consider in the diagnosis.
34 | THE PAIN PRACTITIONER | SPRING 2011
Working to prevent joint destruction and to reduce with biologics in at least half of RA patients. Two
cardiovascular events is also critical in maintaining biologics will not be combined, however, as the increased
full function and, hopefully, in prolonging lifespan. risk of infection is too high.
Categories of agents used to treat RA include disease- The Combinatietherapie Bij Reumatoide Artritis
modifying antirheumatic drugs (DMARDs), nonsteroidal (COBRA) trial looked at sulfasalazine (SSZ) alone
anti-inflammatory drugs (NSAIDs), and steroids. compared to a combination of methotrexate (MTX),
SSZ, and prednisone. The study found that step-down
Treat Early and Aggressively combination therapy was superior to monotherapy (6). In
Historically, RA patients were given low doses of a long-term study of COBRA combination therapy (7),
pharmacologic agents that were increased or changed there was significantly more radiographic damage in the
slowly, but that paradigm has changed dramatically over patients who received monotherapy than in those who
the past 10 years. It is important to treat early to prevent received combination therapy.
damage and disability. Delayed therapy will also lead to
poorer radiological outcomes. The 2010 European League Treat With a Targeted Goal
Against Rheumatism (EULAR) guidelines for treatment Every patient should be treated with remission as the goal,
suggest starting treatment with DMARDs at the time of as in other disease states. If that engenders too much toxicity
diagnosis (4). Some would suggest starting within 6 weeks and is not possible, low disease activity should be the goal.
of the first symptom of RA, not the diagnosis. Treat RA The BeST (Dutch acronym for Behandel-Strategieën,
aggressively by using the maximal efficacious dose of “treatment strategies”) study compared 4 groups of
DMARD, as supported by the literature and as tolerated treatment strategies for RA (8). Group 1 was assigned to
by the patient. The doses of these agents are also rapidly sequential monotherapy, so if patients did not respond to
escalated, instead of the slow process formerly employed. one medication at the highest tolerable dose, it was
replaced with another. This had been the usual treatment
Clinicians treating RA have become strategy for RA. Group 2 had a step-up approach, where
much like oncologists in that now RA patients started with MTX, and additional nonbiologic
DMARDs were added if the response to MTX was
is treated with a combination of inadequate. Group 3 was the opposite of Group 2, in that
agents: nonbiologics can be treatment began with combination therapy, and if
combined with other nonbiologics patients responded well, they could discontinue one of
or with biologics in at least half of the nonbiologics. Group 4 was similar to Group 3, except
that Group 4 had MTX plus a biologic agent while
RA patients Group 3 employed nonbiologics. All of the treatment
strategies were designed to achieve low disease activity.
As seen clinically, patients with active disease states of Over a few years of this study, the mean disability scores
prolonged duration are less responsive to treatment than for the 4 groups, measured by the Health Assessment
those with active disease states of short duration. One Questionnaire (HAQ), were comparable. Although
study (5), involving patients who experienced Groups 3 and 4 achieved the desired outcome more
improvement with treatment, sought to identify factors quickly than Groups 1 and 2, over time the percentages
that affected their response to treatment, and its results of patients achieving low disease outcome were equivalent.
support this finding. Patients with longer disease
durations at the time of treatment initiation experienced Therapeutic Developments in Rheumatoid Arthritis
poorer response rates. There have been 3 landmark developments in the
treatment of RA: corticosteroids in the 1940s; MTX in
Treat With a Combination of Agents (When Appropriate) the 1980s; and TNF inhibitors in 1998. A discussion of
Clinicians treating RA have become much like oncologists these treatments and other DMARDs follows.
in that now RA is treated with a combination of agents:
nonbiologics can be combined with other nonbiologics or
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F E AT U R E | PHARMACOLOGIC APPROACHES TO RHEUMATOID ARTHRITIS
Corticosteroids Commonly Used Disease-modifying
When corticosteroids were prescribed for RA in the 1940s, Antirheumatic Drugs
patients who had been bedridden for years could now Nonbiologics
walk. However, because of the high risk of adverse effects Nonbiologics include hydroxychloroquine, the
(AEs) with corticosteroids and with the introduction of antimetabolites (MTX and leflunomide), and SSZ.
newer agents, their use in RA should be limited to 2 Patients with mild disease and normal radiographic
indications: early in disease when patients are unable to findings may do well with hydroxychloroquine or SSZ.
function and DMARDs may take time to work, and in However, most patients will fare best with MTX, especially
patients who have recalcitrant disease and need a small those with more severe disease or radiographic damage at the
amount of prednisone or who cannot tolerate NSAIDs. time of presentation. The antimetabolites MTX and
leflunomide are DNA synthesis inhibitors. MTX is typically
used before leflunomide, as there are more efficacy data
We learned from laboratory on MTX and it has fewer AEs. SSZ is a combination of
research that TNF-alpha was a modified aspirin and an antibiotic, and it is not known
major driver of inflammation in RA, why it is effective in RA. SSZ is not as strong an agent as
MTX, so the agent of choice is MTX unless contraindicated.
and clinical trials proved that by
targeting this single cytokine, we Biologics
could affect the disease process. Biologics approved for the treatment of RA include TNF
inhibitors, an inhibitor of T-cell costimulation
(abatacept), a B-cell depleting monoclonal antibody
Methotrexate (rituximab), and an anti-IL-6 monoclonal antibody
MTX has been a remarkable agent for RA treatment, as it (tocilizumab). These biologics show that there are many
can be used in relatively low doses, is very effective, and important molecules in the pathogenesis of RA, as each
has a low toxicity profile. MTX is the most commonly one of these biologics has significant efficacy in RA
used first DMARD because of its high benefit-to-risk although no single agent is effective in all patients.
ratio. Patients sometimes express concern when the
pharmacist gives them the printout about oncologic doses Choosing a Second Disease-modifying
that lists terrible AEs, but it is a safe agent overall at the Antirheumatic Drug
doses used in RA. Do not use MTX in patients who have If the patient fails to improve with an initial DMARD,
liver disease or who are pregnant, as it can cause liver the choice of a second disease-modifying agent in part
irritation and birth defects, respectively. depends on how much residual disease activity is present. If
MTX is rapidly dosed. Start at 15 mg once per week, the disease activity is very minor, adding hydroxychloroquine
and increase to 20-25 mg over 2 to 3 months. If there is or an NSAID may be effective. Moderate disease activity
an inadequate response to 20-25 mg MTX, add a second calls for the addition of either a nonbiologic like SSZ or
nonbiologic or biologic DMARD within 1 to 3 months. leflunomide, or a biologic such as a TNF inhibitor or
abatacept, to MTX. If severe residual disease activity is
Anti-Tumor Necrosis Factor Therapy present, a biologic agent should be added. This will usually
TNF inhibitors (9) were the first targeted therapy for RA, consist of a TNF inhibitor. Speed of onset is important—
and 5 are now available: etanercept, infliximab, adalimumab, if the patient has debilitating and excessive residual
golimumab, and certolizumab. RA is one of the diseases disease activity while on MTX, a TNF inhibitor should
whose knowledge has been advanced by the introduction be chosen rather than a nonbiologic that takes more time
of targeted therapy. We learned from laboratory research to produce effects. This choice also depends on the
that TNF-alpha was a major driver of inflammation in relative efficacy; unfortunately, there are few comparative
RA, and clinical trials proved that by targeting this single effectiveness trials, so those data are not available.
cytokine, we could affect the disease process. Relative cost of the agent is very important.
Methotrexate costs about $1000 to $1500 per year while
TNF inhibitors cost about $24,000 per year, and
36 | THE PAIN PRACTITIONER | SPRING 2011
infliximab costs up to $30,000 per year, depending on the PPD is greater than 5 mm, which is considered positive
dose used. This difference is often why nonbiologics are in this context, a chest x-ray is necessary to rule out active
used more frequently. The approval of a third-party payor disease. A negative PPD but a history of exposure to TB
may also determine which agent is used. should trigger a consultation with your local infectious
disease expert regarding advisability of treatment for
Tumor Necrosis Factor-alpha Inhibitors possible latent TB.
The 5 currently available TNF-alpha inhibitors improve
signs and symptoms of disease, so that many patients Options after Tumor Necrosis Factor Inhibitor Failure
have less joint pain and less swelling. The ESR and CRP Although TNF inhibitors are generally efficacious, in
rapidly improve, and radiographic progression is slowed clinical trials only 50% of patients experienced a mild-to-
or prevented. Monotherapy with TNF inhibitors is moderate response, so these agents are not the answer for
slightly more efficacious than monotherapy with MTX, all patients (12). In the case of treatment failure with one
primarily in the radiographic realm. However, TNF inhibitor, switching to a different TNF inhibitor has
combination treatment with a TNF inhibitor and MTX been shown to be efficacious in some individuals. If the
is more efficacious than either agent alone. patient fails 2 TNF inhibitors, it is time to try a different
class of agents: abatacept, rituximab, or tocilizumab.
To preempt the development of
tuberculosis from a TNF inhibitor, a Abatacept
Abatacept (Orencia) has been moderately to modestly
purified protein derivative (PPD) test
efficacious as a monotherapy, in MTX failures (13), and
is mandatory before treatment in TNF-inhibitor failures (14). Although abatacept
initiation, even if the patient interferes with only one of the many costimulatory
received Bacille Calmette Guerin interactions of T cells with antigen-presenting cells and
works more slowly than the TNF inhibitors, it is still
(BCG) vaccination as a child. efficacious. Recent data on several safety issues—risk of
TB infections, suppression of response to immunizations,
The efficacies of the 5 agents appear to be and risk of malignancy—suggest that these are relatively
comparable, although no head-to-head comparisons have low in patients treated with abatacept, consistent with
been conducted (9,10). Toxicities are comparable as well incidence using other biologics (15).
with one caveat: more opportunistic infections are likely
with infliximab and possibly with adalimumab (11). Rituximab
TNF inhibitors are contraindicated in patients who Rituximab (Rituxan) is the only FDA-approved B-cell
have recurrent bacterial infections and in patients who therapy for RA, and it is directed against CD20 on the
have untreated latent or active tuberculosis. There are surface of B cells. It has shown modest efficacy as a
also concerns about whether TNF inhibitors cause monotherapy and moderate efficacy in combination with
malignancy, particularly lymphoma. RA itself is associated MTX for patients who have not adequately responded to
with the development of lymphoma, so if a TNF MTX (16) or a TNF inhibitor (17). Currently, rituximab
inhibitor is added, it becomes difficult to tell if the is approved only for patients who have failed treatment
lymphoma developed from RA itself or from the with TNF inhibitors, and not as a monotherapy. Its safety
treatment. TNF inhibitors should not be prescribed for profile is relatively good, but there are limited data on
patients with multiple sclerosis or other demyelinating long-term follow-up.
diseases and patients with uncompensated heart failure. Clinical response to rituximab is unrelated to the
To preempt the development of tuberculosis from a rapidity of depletion of B cells in the blood and flare does
TNF inhibitor, a purified protein derivative (PPD) test is not appear to be related to rapidity of repletion of B cells
mandatory before treatment initiation, even if the patient in the periphery. Some data, however, suggest that clinical
received Bacille Calmette Guerin (BCG) vaccination as a response corresponds with B-cell populations within the
child. If the PPD is negative and there is no history of synovium, not in the bloodstream (18). RF seropositive
exposure, it is generally safe to use a TNF inhibitor. If the
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F E AT U R E | PHARMACOLOGIC APPROACHES TO RHEUMATOID ARTHRITIS
patients have also been shown to respond better to increase lipid levels. Almost all biologics will raise lipid
treatment with rituximab than seronegative patients (19). levels, because inflammation actually reduces lipid levels.
Repeated courses of rituximab lead to immunoglobulin Data from the Mayo Clinic have shown that as patients
depletion. Over time, with repeated infusions, the IgG develop RA and progress from the preclinical state into
and IgM levels start to decrease and should be the clinical state, their lipid levels decrease (28). As they
monitored. The development of progressive multifocal are treated, no matter which agent they are using, lipid
leukoencephalopathy (PML) is also possible but extremely levels start to increase again. Therefore, this effect of TCZ
rare. In most cases where PML developed in RA patients is probably related to its control of the inflammation, but
taking rituximab, the patients were also receiving it still must be monitored because of the risk of
immunosuppressive agents for cancer (20). cardiovascular disease in RA (29).
Belimumab and Atacicept
Another approach has been to target growth factors for B Amazing developments in treating RA have taken place
cells, to suppress the progression of B cell development over the last 10 to 12 years. Patients can now be diagnosed
from progenitors to plasma cells (21). These agents target with RA and expect to live functional lives, unlike 15 to
2 cytokines that sustain B cell activation, B lymphocyte 20 years ago. Despite these advances, 4 fundamental
stimulator (BLyS) and a proliferation-inducing ligand issues remain: the cause of RA is unknown; there is no
(APRIL) (22). Both belimumab and atacicept have been method to predict who will be afflicted; no cure is
ineffective in phase 2 RA trials. The fact that anti-CD20 known; and no preventive measures are available. These
approaches work but inhibition of B cell growth factors aspects should be the focus of study in the next decade. I
does not is curious and, to date, unexplained (23).
JOAN M. BATHON, MD, is a
Tocilizumab rheumatologist and Director of the
Tocilizumab (TCZ), an antibody directed against the IL-6 Division of Rheumatology at Columbia
receptor, is approved for RA patients who have failed TNF University in New York City. Dr. Bathon is
inhibitors. The induction of IL-6 by TNF explains systemic a clinical researcher who focuses on
manifestations of inflammation, including the acute phase mechanisms of inflammation and joint
response (CRP, ESR), anemia (through the induction of destruction in RA and osteoarthritis.
hepcidin), hypergammaglobulinemia, and hypoalbuminemia. She is the principal investigator of several
This IL-6 signature is not specific to RA, but it is present federal and nonfederal grants to study the role of inflammation
in any chronic inflammatory disease, infectious or not. in mediating susceptibility of RA patients to accelerated
TCZ is an effective inhibitor of IL-6 that has been cardiovascular disease. Dr. Bathon has written more than 110
shown to improve signs and symptoms of RA at all stages publications on inflammatory and degenerative arthritis. She is
of disease (24). It also improves physical function and the Editor-in-Chief of Arthritis & Rheumatism. She recently
quality of life, as do the other biologics, improves completed a term on the FDA Arthritis Advisory Committee.
hemoglobin levels, and modifies disease activity (25).
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Dr Bathon’s article was based on her presentation at the 2010 Annual
Clinical Meeting. For those of you who are interested in rheumatology
and/or pharmacology, you might find the following presentations at the
2011 meeting particularly useful:
Practical Approaches to Fibromyalgia Diagnosis, with Afton Hassett, PsyD
Pharmacologic Approaches to Neuropathic Pain, with Marco Pappagallo, MD
Rational Polypharmacy, with Kathryn L. Hahn, PharmD
To register, please visit www.aapainmanage.org or call 209-533-9744.
THE PAIN PRACTITIONER | VOLUME 21, NUMBER 1 | 39