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The management of patients with RA has changed considerably over the past several years. The introduction of new DMARDs
prompted the emerging trend among rheumatologists to treat RA patients earlier and more aggressively.
The ultimate goal in managing RA is to prevent structural joint damage and loss of function. Recent evidence suggests
that early intervention is important in achieving this goal. In this new management setting, more attention is given to the
differentiation between RA and other types of arthritis, particularly osteoarthritis.
Initial evaluation of RA patients should include the risk of developing self-limiting arthritis, persistent nonerosive
arthritis, and persistent erosive arthritis. In addition, strategies aimed at providing access to optimal medical care for
this patient population need to be addressed.
To reduce the progression of RA, the vast majority of RA patients should be treated with DMARD therapy shortly after
the diagnosis. An accurate method of monitoring disease activity is needed to assess the effect of this therapy.
Rapid and sufficient control of disease activity is needed to prevent joint damage, loss of function, and to maintain
quality of life. Combination DMARD therapy may, in this respect, provide additive effects or allow dose reductions to avoid
toxicity. Optimal management also includes patient education and the involvement of a multidisciplinary team of health care
providers to minimize the impact of the disease on the individual's functional activity. The following is a discussion of
these issues in the treatment of RA patients.
Because DMARD treatment is justified only when the risk benefit is favorable, it is mandatory to differentiate between
RA and other forms of arthritis as early as possible after the development of symptoms. The 1987 American College of Rheumatology
(ACR) criteria for RA have often been used as a diagnostic tool in patients with recent-onset arthritis. However, these criteria
were not developed in patient populations in need of a diagnosis, and therefore the diagnostic ability in early RA is likely
to be suboptimal.
In a collaborative effort, several groups involving data sets of patients with early arthritis are developing diagnostic
criteria. In these studies, the gold standard for diagnostic indicators will be defined by the clinical outcome after years
of follow-up. This activity will provide a set of criteria that will allow discrimination between self-limiting, persisting
nonerosive, and persistent erosive arthritis early in the course of the disease. An internationally accepted diagnostic model
will allow construction of a therapeutic algorithm in which levels of probability for persistent arthritis are linked with
choices for DMARD treatment.
Poor prognosis with respect to joint destruction is suggested by early age of RA onset, high titer of rheumatoid factor,
high levels of acute-phase proteins, high numbers of involved joints, and early occurrence of joint erosions. The presence
of these factors indicates a 75% probability that clinically significant joint damage will occur. The ability to predict joint
damage can be improved; however, current predictors are already influencing therapeutic choices.
Monitoring of RA: Accurate monitoring of disease progression is mandatory to assess therapeutic efficacy of agents that
slow or inhibit structural joint damage and limit long-term disability. Because of the heterogeneity in disease progression
between individual patients, a composite evaluation of a variety of clinical parameters is needed. The selection of an evaluation
index should be governed by parameters sensitive to changes that are easy to obtain, are not redundant, and have high predictive
attributes for long-term disease outcome.
Both the European League Against Rheumatism and the ACR have defined core sets of disease activity measures for RA with
the goal of providing uniformity in the assessment of outcome in clinical trials. These measures include tender and swollen
joint counts, patient and physician global assessments of disease activity, acute-phase reactants, and pain and physical disability
assessments. Each core set has proven viability and reliability, and has a high level of agreement.
However, these core sets have limitations. The ACR 20% response criteria (ACR20) are composed of a combination of ratios
and do not provide an absolute measure of changes in activity. Additionally, the European League Against Rheumatism Disease
Activity Score is complex. Because of these limitations, these indices have not been introduced into day-to-day clinical practice
for the assessment of RA treatment.
To avoid these limitations, Smolen et al.recently proposed a simplified disease activity score (DAS). Using the sum score
of the tender and swollen joint counts (28 joints), patient and physician global assessments of disease activity, and the
C-reactive protein level, high correlations are obtained with validated measures. This simplified index may be a viable supplement
to the core sets and can be implemented in daily clinical practice. In addition, when used in clinical trials, this index
would have an intuitive familiarity, thereby allowing the practitioner to compare the results of clinical trials with familiar
clinical observations.
Pharmacologic treatment: The initial drug treatment for RA involves the use of salicylates, nonsteroidal anti-inflammatory
drugs, or selective cyclooxygenase-2 inhibitors to reduce pain and improve motion. Low-dose oral glucocorticoids and local
injections of glucocorticoids are highly effective for relieving symptoms in patients with active RA, and prolonged treatment
appears to have disease-modifying properties.
However, because these agents do not affect disease progression, they should not be used as monotherapy in RA. All RA
patients are therefore candidates for DMARD therapy to prevent structural joint damage and maintain function. Furthermore,
referral from a primary care physician to a rheumatologist is recommended in the event of clinical suspicion, as delay induced
by the desire for a confirmation of a diagnosis often results in disease progression before effective treatment is initiated.
Early initiation of DMARD therapy is advocated to prevent irreversible structural joint damage. Van der Heijde reported
that approximately 75% of RA patients with early disease have joint erosions or develop erosions within the first 2 years
after the onset of symptoms. Three studies have compared the use of early single-DMARD treatment with the delayed approach
and reported that early introduction of DMARD therapy is associated with a better outcome after 1 or 2 years of treatment.
Furthermore, a recent evaluation of primary data from 14 randomized clinical trials in RA patients indicates that patients
with a longer disease history do not respond to DMARD therapy as well as patients treated at earlier stages of the disease.
Importantly, major side effects of early DMARD treatment are manageable, which supports the conclusion that all early RA patients
should be treated with DMARDs. The large majority of RA patients are eventually subjected to the potential side effect of
DMARD therapy; it is thus pointless to delay early treatment that may improve long-term outcome. Early DMARD treatment may
also result in reduced total health care costs.
The DMARDs most frequently used include methotrexate (MTX), sulfasalazine,
hydroxychloroquine, and leflunomide. The choice of a DMARD for an individual patient is based on many factors, including the
efficacy/toxicity spectrum of a drug, monitoring requirements, costs, and patient variables such as prognosis, comorbidity,
and preferences. MTX has a prominent place in the therapeutic armamentarium of many rheumatologists. A generally accepted
guideline for MTX use is that the drug should be prescribed as monotherapy when initial treatment with another DMARD has not
achieved disease control. On failure of MTX monotherapy, combination therapy with MTX and other DMARDs is considered for the
next line of therapy.
The most recently approved DMARD is leflunomide (Arava; Aventis Pharmaceuticals, Kansas City, MO, USA), a pyrimidine
synthesis inhibitor that has both immunosuppressive and immunomodulatory effects. Leflunomide inhibits T-cell proliferation,
autophosphorylation of epidermal growth factor receptors, and activation of nuclear factor-?B. The efficacy of leflunomide
was investigated in three large, phase III clinical trials. Leflunomide significantly increased the proportion of patients
who experienced an ACR20 score and significantly improved tender joint counts, swollen joint counts, and physician and patient
global assessments compared with placebo. However, MTX and sulfasalazine were found to be as effective as leflunomide.
Common adverse events associated with leflunomide included gastrointestinal disorders, alopecia, skin rash, and elevated
liver enzymes. Nevertheless, given the comparable efficacy and the improved safety profile of leflunomide ,in some patients,compared
with MTX, many physicians regard leflunomide as a good alternative,especially those patients who cannot tolterate MTX.
Many rheumatologists already prescribe combination therapy even though evidence to support combination therapy was limited
until recently. Three main strategies are often used in combining DMARDs, and include parallel, step-up, and step-down regimens.
Data from an increasing number of trials that support combination therapy have recently been completed. Step-down bridge
therapies that include corticosteroids have been shown to provide enhanced efficacy with low toxicity. In patients with a
long history of disease, leflunomide improved a suboptimal response to MTX alone, and the triple combination of MTX, sulfasalazine,
and hydroxychloroquine appears to be clinically superior compared with the agents used in monotherapy,without increased toxicity.
Because of the immunosuppressive properties of DMARDs, the combination of leflunomide with MTX or any other immunosuppressive
agent needs to be closely monitored. Indeed, most of the rare reports of pancytopenia in patients receiving leflunomide occurred
in patients who had recently discontinued or were receiving concomitant immunosuppressive agents. Further studies are required
to determine whether any combination of DMARD therapy provides improved efficacy. Many new therapeutic strategies are being
investigated for RA.
Reconstructive surgery can provide great improvement for patients with end-stage joint damage that is causing unacceptable
pain or limitation. However, despite the achievements of pharmacologic and surgical treatment, many patients are left with
residual disability. Regular participation in conditioning exercise programs improves mobility, strength, and well-being,
and does not increase arthritis activity. RA patients may therefore benefit from a variety of rehabilitation programs.
Recent evaluations suggest that physical therapy, occupational therapy, psychosocial support, and the care of nurse practitioners
and orthopedic surgeons is more effective when given by a multidisciplinary team. The additional value of team care may be
explained by enhanced communication, the specific mix of professional expertise, and the increased attention provided to the
patient. Dynamic and fast-growing insights into cell biology and the understanding of inflammation have resulted in a new
appreciation of the pathophysiology of RA. It is now believed that RA is mediated by a vast array of cells and soluble factors
that recruit immune cells and perpetuate inflammation. Although the primary antigen is unknown, the initial autoimmune response
is associated with an infiltration of T lymphocytes that secrete chemotactic agents, particularly TNF-a and IL-1.
These chemotactic agents recruit lymphocytes, macrophages, and B cells to the synovial interstitium of the joint. Extracellular
signals also activate complex intracellular signaling pathways, alter messenger RNA synthesis, and increase the production
of pro-inflammatory cytokines. Increases in pro-inflammatory cytokines lead to further cell recruitment of macrophages
and the activation of synovial fibroblasts, chondrocytes, and endothelial cells in a synovial capsule. Activation of these
cell types further increases cell migration to the area, and leads to more inflammation, cartilage degradation, and increased
bone resorption.
Developments in molecular biology and computational chemistry have allowed the design of agents that specifically target
pro-inflammatory cytokines. IL-1 is elevated in the synovial fluid of RA patients and is thought to contribute to the pathophysiology
of the disease. IL-1 receptor antagonist is a naturally occurring cytokine that competes with IL-1 for binding to the
IL-1 type 1 receptor, but does not initiate the IL-1 signaling transduction cascade on binding to the IL-1 type 1 receptor.
Fujikawa et al. demonstrated that IL-1 receptor antagonist production is reduced in synovial cells isolated from RA patients.
Anakinra (Kineret; Amgen, Thousand Oaks, CA, USA), a recombinant nonglycosylated form of IL-1 receptor antagonist, is
an approved therapy for RA patients. The efficacy and safety of anakinra was demonstrated in three double-blind trials. In
those studies, patients treated with anakinra experienced significant improvements in tender and swollen joint counts, pain
scores, morning stiffness, and radiographic progression.
Anakinra treatment was associated with injection-site reactions, a higher incidence of neutropenia compared with placebo,
and an increased risk of infection. Interestingly, neutralizing concentrations of IL-1 receptor antagonist reduced the production
of IL-6 and IL-8, but not TNF-a, in rheumatoid synovial membrane cultures. In contrast, anti-TNF-a antibodies neutralized
not only TNF-a levels, but also IL-6, IL-8, and IL-1 levels, suggesting that TNF-a may play a more central role in the pathophysiology
of RA.
This apparent central role of TNF-a has led to the development of a new class of agents (anti-TNF antagonists) that includes
infliximab (Remicade®; Centocor, Malvern, PA, USA), a chimeric monoclonal antibody specific for TNF-a, and etanercept (Enbrel;
Immunex, Seattle, WA, USA), a fusion protein of the p75 TNF receptor and immunoglobulin G1. Anti-TNF antagonists have been
shown to inhibit the development of polyarthritic disease in collagen-induced arthritic mice and in mice that constitutively
express human TNF-a.
Etanercept exhibits a lower specificity than infliximab and binds to both TNF-a and lymphotoxin-a . Nevertheless, the
efficacy of etanercept in the treatment of RA patients was demonstrated in several phase II/III studies. Moreland et al. reported
that, at 3 months, patients treated with etanercept achieved significant improvement in swollen and tender joint counts, morning
stiffness, physician and patient assessment scores, erythrocyte sedimentation rate, and quality of life.
Further evidence to support the use of etanercept in the treatment of RA has been reported by Weinblatt et al. In
that study, 71% of patients treated with 25 mg/week etanercept achieved an ACR20 score at week 24 compared with 27% of patients
treated with placebo (P < 0.001). Bathon et al. also reported a significant increase in the number of etanercept-treated
patients achieving an ACR20 compared with MTX in patients with early RA. However, no advantage was seen for etanercept at
6 months. Nevertheless, etanercept slowed joint damage in patients with early RA by significantly reducing joint erosion,
although no benefit on joint space narrowing was observed.
Infliximab has also been shown to be effective in the treatment of RA patients. In a phase II trial (ATTRACT study),
428 patients with active RA despite MTX were treated with or without infliximab. Significant improvements in swollen and tender
joint counts and rheumatoid factor and C-reactive protein levels occurred at 30 weeks, and were maintained through week 54.
In addition, response to treatment occurred rapidly, with approximately 90% of the ultimate responders achieving an ACR20
after only two treatments (6 weeks). This improvement in clinical score was maintained through week 54.
Importantly, infliximab significantly inhibited joint erosion, joint space narrowing, and total radiographic score progression
at 54 weeks and through week 102 (P < 0.001). Clearly, anti-TNF therapy provides significant benefit to patients with RA.
However, because TNF is a normal component of the immune system, some investigators have questioned whether blockade of TNF
could lead to an elevated risk of infection. Although infections are more common in the RA population relative to the general
public, there is a concern that anti-TNF therapy may increase serious infections.
Indeed, serious infections and sepsis have been reported in postmarketing reports in patients treated with etanercept
and infliximab. Furthermore, rare cases of tuberculosis have been reported in patients treated with TNF antagonists. Nevertheless,
with proper screening and care in observing patients susceptible to infections, anti-TNF therapy can provide the benefits
of reduced structural joint damage and improved quality of life for the majority of RA patients. According to international
consensus, patients are candidates for treatment with biologic agents if DMARD treatment fails to achieve disease control
.Nevertheless, studies in selected areas of efficacy, toxicity, and the general use of TNF antagonists are still needed
to help further define the most appropriate use of these agents. The success of TNF inhibitors in treating RA suggests that
inhibition of other upstream and downstream members of extracellular and/or intracellular signaling cascades may also prove
to be of therapeutic benefit. At present, biologic agents have been shown to be effective and have the advantage of specificity
over other agents, such as DMARDs. However, the development of nonbiologic inhibitors with improved safety profiles compared
with current DMARDS may lead to improved outcomes and reduced costs.
Earlier DMARD treatment and the use of new biologic agents such as the TNF and IL-1 antagonists have begun to alter the
treatment practices of rheumatologists. Further experience in the use of these, and of agents not yet developed, alone and
in combination with DMARDs, is likely to lead to further changes in the manner in which rheumatologists treat this debilitating
disease.
How effective are the traditional DMARDs versus biologic preparations? The ERA trial is the only study that has addressed
this question. In the first year of this trial, 632 patients with early RA were treated with either twice-weekly subcutaneous
etanercept (10 or 25 mg) or weekly oral MTX (mean dose = 19 mg/week) for 12 months. Study results showed that the effectiveness
of MTX was very similar to that of etanercept.
There are several studies (some available only as abstracts) that have demonstrated the effectiveness of biologic DMARDs
in patients who responded suboptimally to MTX (dosed at less than or equal to 20 mg/week with no patients switched from oral
to either subcutaneous or intramuscular administration). These results make it difficult for the clinician to judge the relative
effectiveness of the new preparations vs traditional DMARDs.
However, review of the literature suggests that treating patients who responded suboptimally to MTX with other traditional
DMARDs or combinations of these drugs may be as effective as administration of biologic preparations. A critical question
in the long-term treatment of patients with RA is whether an aggressive, early, and temporary intervention can provide long-term
benefit in patients with this disease. The results of the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial have
provided some insight with respect to this issue. The initial phase of this study demonstrated that step-down combination
therapy with prednisolone, MTX, and SSZ was superior to SSZ monotherapy for suppressing disease activity and radiologic progression
of RA. Additional 4- to 5-year follow-up of these patients during treatment (all received "best available" therapy) showed
that the patients who received combination therapy as initial treatment had significantly less disease progression than those
treated with SSZ alone. Thus, initial intensive combination treatment that included very short-term high-dose corticosteroids
resulted in sustained suppression of radiologic progression in patients with early RA, independent of subsequent antirheumatic
therapy.
Many RA patients will experience disease progression, particularly when treated with any single agent, and will require
additional therapy to manage their clinical symptoms. A number of treatment options have proven effective for such patients,
most of which entail the continuation of MTX therapy and/or addition of other DMARDs. Both HCQ and SSZ are highly effective
when used in combination with MTX and results reviewed above strongly support use of the triple combination of MTX, HCQ, and
SSZ in patients who have had a suboptimal response to MTX. Other potentially effective combinations include MTX plus either
cyclosporine or leflunomide, or MTX combined with etanercept, infliximab, or adalimumab. Comparison trials of these approaches
are sorely needed.
Clinicians support the view that most patients with RA should be initially treated with MTX with rapid dose titration
to 20 to 25 mg/week and switched to subcutaneous administration if oral therapy is not effective. If such treatment does not
yield a satisfactory response, SSZ and HCQ should be added to the regimen. Biologic agents can and should be added, preferably
within the first year after diagnosis, if patients have not responded in a satisfactory fashion to optimal combination DMARD
therapy.
Effectiveness of biologic DMARDs in the treatment of early RA. Early effective treatment of RA is particularly important
for slowing and even potentially halting disease progression. The results of Genovese and colleagues provide strong support
for the use of etanercept, the human recombinant version of TNFR1 that is linked to the Fc receptor of human immunoglobulin
G1 (IgG1), in patients with early RA. These investigators compared clinical and radiographic outcomes in 632 patients who
received monotherapy with either etanercept or MTX for 2 years. Following at least 1 year of double-blind treatment, 512 patients
continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. At
the end of 2 years, patients who received 25 mg etanercept twice weekly had a higher ACR20 response rate than patients who
received 20 mg/week MTX.
The monoclonal antibody drug adalimumab (Humira) is now approved as a first-line treatment for moderate to severe rheumatoid
arthritis (RA). Humira can be used either alone or in combination with methotrexate (Rheumatrex) or other disease modifying
anti-rheumatic drugs (DMARDs).
Treatment Research
- Newly diagnosed patients may be best treated by combining DMARDs with either tumor necrosis factor (TNF) modifiers or
steroid drugs. A 2005 study found that DMARDs combined with either infliximab (Remicade) or prednisone (Deltasone, Orasone)
worked better in preventing joint damage in early RA than DMARDs alone or step-up combination therapy.
- Patients recently diagnosed with RA may experience a milder form of the disease than patients in previous decades, suggests
a 2005 study. Researchers analyzed trends in symptoms and disease activity in patients treated since 1985. Aggressive early
treatment with methotrexate and prednisone may have helped reduce RA severity.
- Folic acid supplements may reduce the effectiveness of methotrexate.
- TNF modifiers and prednisone may increase the risk of developing non-melanoma skin cancer.
- The steroid drug betamethasone (Diprolene) does not help reduce infliximab injection reactions.
Investigative Drugs
- Rituximab (Rituxan/MabThera) combined with methotrexate improves RA symptoms much better than methotrexate alone, according
to Phase III research presented at the American College of Rheumatology (ACR) annual meeting. In a study of over 500 patients,
51% of patients treated with rituximab and methotrexate achieved significant symptom improvement, compared with 18% of patients
treated only with methotrexate.
- Tocilizumab (Actemra) works better than DMARDs in slowing joint damage, according to Phase III trial results presented
at the ACR annual meeting.
Risk Factors and Complications
- Patients with RA are four times more likely to develop non-Hodgkin’s lymphomas than healthy patients, suggests a
2005 review in the Archives of Internal Medicine.
- RA increases the risk for premature delivery and hypertension during pregnancy
People with RA need both exercise and rest. It's important to realize that rheumatoid arthritis cannot be controlled by
vigorous exercise alone and that fragile joints need special protection. But rest is good for a joint with active RA, and
exercise is good for the surrounding muscles.
People with RA need to maintain a balance between rest and exercise. The course of the disease will fluctuate. There will
be times when the joints are more warm, swollen, and painful. There will be other times when the joints feel better and no
longer are warm or swollen. During these times you'll generally feel better and have less fatigue and morning stiffness. Exercise
and activity need to be adjusted to suit these two different situations.
Rest
When the joints are warm and swollen, rest will help to settle the disease down. At times like this it is necessary to
rest more, to do less unnecessary walking, participate in fewer activities, etc. Though reducing activity, you should still
maintain joint mobility by doing range-of-motion exercises.
These are light exercises, done without any weights and designed to preserve the mobility in the painful joint. The joint
should be taken through a full range of motion each day, paying special attention to the end of the motion where the mobility
is lost.
Ease the joint fully to the limit of range. Aquatic exercise usually can be continued at these times as the buoyancy of
the water protects the joints from rapid or stressful movement.
Exercise
When the disease settles down and the joints become less warm and swollen, fatigue diminishes, and morning stiffness reduces,
you should do more.
Range-of-motion exercises should be continued on a daily basis to maintain or restore motion, but strengthening exercises
also should be done. These exercises should be instructed by a therapist.
The purpose is to rebuild the strength of muscles that have weakened during the acute phase of the disease. Strong muscles
are important in providing support to joints and can be built with exercise.
These strengthening exercises, however, have to be modified for people with damaged joints.
Evidence suggests that people with RA can become aerobically fit and that this may help improve stamina, reduce fatigue,
reduce pain and even help depression if present!
Aerobic exercise has not been shown to increase the joint inflammation when done properly. An aerobic program should be
developed under the direction of a care provider and a physical therapist especially for those people with more serious disease.
Occupational and physical therapy
Therapy treatments are helpful for most individuals with rheumatoid arthritis. Physical therapists can teach you how to
exercise appropriately for your physical capabilities.
They will give you valuable instruction on how best to use heat and cold treatments to reduce joint stiffness and swelling
and make movement easier. At times therapists may use special machines to apply deep heat or electrical stimulation to reduce
pain or improve joint mobility.
Occupational therapists construct splints for the hand and wrist and teach people how to best protect and use their joints
when they are affected by arthritis. They also show people how to better cope with day-to-day tasks at home and work, despite
limitations that may be caused by RA.
Sometimes this includes the use of practical tools and items that help individuals perform their day-to-day activities.
It is important to remember that people with RA can and should be able to do most of the normal or usual things everyone else
can, except that it takes them a little bit longer to do it.
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