Pharmacologic Approaches to Rheumatoid Arthritis

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     Pharmacologic Approaches to
     Rheumatoid Arthritis

     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.

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

                                                                       THE PAIN PRACTITIONER | VOLUME 21, NUMBER 1 |              35

     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

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

                                                                       THE PAIN PRACTITIONER | VOLUME 21, NUMBER 1 |             37

     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).
     Also, radiographic data have suggested that TCZ can slow       REFERENCES
     progression of radiographic damage in patients at high
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         Surprisingly, one possible adverse effect of TCZ is
                                                                    2.   Arnett FC, Edworthy SM, Bloch DA, et al. The American
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                                                                    4.   Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations
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5.   Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting       17. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for
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     2002;46(2):347-356.                                                         rituximab and timeframe to relapse in rheumatoid arthritis patients:
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    2004;63(Suppl 1):i138.                                                       effective in slowing radiographic progression in patients with
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    rheumatoid arthritis: a review. Clin Ther. 2010;32(11):1855-1870.        28. Myasoedova E, Crowson CS, Kremers HM, Fitz-Gibbon PD,
16. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy          Therneau TM, Gabriel SE. Total cholesterol and LDL levels decrease
    and safety of rituximab in patients with active rheumatoid arthritis         before rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1310-1314.
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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 or call 209-533-9744.

                                                                                     THE PAIN PRACTITIONER | VOLUME 21, NUMBER 1 |                         39

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